|
1
|
Chuang HN, Pei W, Kuo TF, Liu YH, Wang CY, Chang YW, Chuang C, Yang CH, Chuang MH. Effect of injecting adipose stem cells combined with platelet-rich fibrin releasate at Shenshu acupoint (BL23) on acute kidney injury in rabbits. Front Pharmacol 2025; 16:1409056. [PMID: 40144656 PMCID: PMC11936987 DOI: 10.3389/fphar.2025.1409056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 02/19/2025] [Indexed: 03/28/2025] Open
Abstract
Introduction Acute kidney injury (AKI) is a major and unmet medical need, characterized by a sudden onset of kidney dysfunction that often occurs within 7 days. Adipose-derived stem cells (ADSCs) are known for their regenerative, differentiative, and repair abilities, making them a promising therapeutic option for kidney injury. Platelet-rich fibrin releasate (PRFr), derived from platelet-rich fibrin after static incubation, contains numerous growth factors that may promote the differentiation and proliferation of stem cells. Additionally, acupoints such as Shenshu (BL23) have been used in clinical practice and experimental settings, particularly in renal failure treatments. Methods This study aimed to evaluate the synergistic effects of ADSCs and PRFr, administered separately or in combination, at the Shenshu acupoint (BL23) in New Zealand white rabbits with acute kidney injury. The treatment groups were injected with ADSCs, PRFr, or a combination of both. Serum creatinine (CRE) and blood urea nitrogen (BUN) levels were measured to assess kidney function. Additionally, histological examination of kidney tissue was performed to observe morphological changes and tissue repair. Results The PRFr + ADSCs treatment group exhibited a significant reduction in CRE and BUN levels during the second week following transplantation. After 7 weeks of treatment, the PRFr + ADSCs group showed the most favorable kidney repair outcomes, with intact glomeruli, no edema or vacuole-like changes in the renal tubular epithelial cells, and no significant infiltration of inflammatory cells in the surrounding tissues. Discussion The administration of PRFr, ADSCs, and their combination at the Shenshu acupoint (BL23) demonstrated a potential therapeutic effect in repairing damaged renal cells, improving kidney function, and reducing serum CRE and BUN levels. These findings suggest that injection of PRFr, ADSCs, and their combination at the Shenshu acupoint (BL23) can effectively repair damaged renal cells and improve kidney function in AKI. The observed synergistic effect indicates that this approach holds potential as a novel therapeutic strategy for kidney injury. Further research is needed to optimize treatment protocols and elucidate the underlying mechanisms.
Collapse
Affiliation(s)
- Hsin-Ni Chuang
- Ph.D. Program of Management, Chung Hua University, Hsinchu, Taiwan
| | - Wen Pei
- College of Management, Chung Hua University, Hsinchu, Taiwan
| | - Tzong-Fu Kuo
- School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Hao Liu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chia-Yih Wang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yen-Wei Chang
- Department of Physical Education, Asia University, Taichung, Taiwan
| | | | - Chang-Huan Yang
- Gwo Xi Stem Cell Applied Technology Co., Ltd., Hsinchu, Taiwan
| | - Ming-Hsi Chuang
- College of Management, Chung Hua University, Hsinchu, Taiwan
- Gwo Xi Stem Cell Applied Technology Co., Ltd., Hsinchu, Taiwan
- Institute of Biopharmaceutical Science, National Yang Ming Chiao Tung University, Taipei, Taiwan
- School of Public Health, National Defense Medical Center, Taipei City, Taiwan
| |
Collapse
|
|
2
|
Zhang J, Hu F, Zhang J, Xie J, Wang Z, Lv L, Liang H, Liu Q, Chen R, Li H, Su W, Yan R, Chen Z, Wang Z, Tang H, Chang YN, Li J, Chen J, Shen M, Xing G, Chen K. Physical-Matched Nanoplatelets Boost Heterogeneous Thrombi Targeting Through Self-Adaptive Deformation for Thrombolysis and Endothelial Repairing. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2406262. [PMID: 39428893 DOI: 10.1002/smll.202406262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/14/2024] [Indexed: 10/22/2024]
Abstract
The heterogeneity of thrombi in terms of composition, structure, and blood rheology parameters presents a challenge for effective thrombus-targeting drug delivery. To address this, a self-adaptive nano-delivery system, termed D-PLT, is developed. It consists of platelet membrane-cloaked deformable mesoporous organic silicon dioxide nanocomposite, enabling it to respond to the challenge of the heterogeneity of thrombi in arteries and veins. The system exhibits progressive targeting, with the ability to target arterial and venous thrombosis and damaged blood vessels. D-PLT physically matches the pore structure of the thrombus by undergoing varied deformation, leading to advanced targeting and enrichment of arterial and venous thrombus. When co-loaded with the thrombolytic drug urokinase (UK) and the endothelium-protecting agent atorvastatin calcium (AT), the system improves rapid vascular opening of arterial and venous thrombosis in 90 min and provides up to 7 days of durable thrombolysis and recovery from endothelial dysfunction in vivo. This self-adaptive delivery system offers a promising strategy to overcome thrombus heterogeneity.
Collapse
Affiliation(s)
- Junhui Zhang
- Department of Biochemistry and Molecular Biology, Yanbian University Medical College, Yanji, Jilin, 133002, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Fan Hu
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Junzhe Zhang
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China
| | - Jing Xie
- State Key Laboratory of Explosion Science and Safety Protection, Institute of Technology Beijing, Beijing, 100081, P. R. China
| | - Zhiyu Wang
- State Key Laboratory of Explosion Science and Safety Protection, Institute of Technology Beijing, Beijing, 100081, P. R. China
| | - Linwen Lv
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Haojun Liang
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Qiuyang Liu
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Ranran Chen
- Department of Biochemistry and Molecular Biology, Yanbian University Medical College, Yanji, Jilin, 133002, China
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Hao Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Wenxi Su
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Ruyu Yan
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Ziteng Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Zhijie Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Hongyu Tang
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Ya-Nan Chang
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Juan Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Jun Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
| | - Minghua Shen
- Department of Biochemistry and Molecular Biology, Yanbian University Medical College, Yanji, Jilin, 133002, China
| | - Gengmei Xing
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| | - Kui Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterial & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China
- Guangdong-Hong Kong-Macao Joint Laboratory for Neutron Scattering Science and Technology, Spallation Neutron Source Science Center, Dongguan, 523803, China
| |
Collapse
|
|
3
|
Lee CK, Wang FT, Huang CH, Chan WH. Prevention of methylmercury-triggered ROS-mediated impairment of embryo development by co-culture with adult adipose-derived mesenchymal stem cells. Toxicol Res (Camb) 2024; 13:tfad122. [PMID: 38162594 PMCID: PMC10753290 DOI: 10.1093/toxres/tfad122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/19/2023] [Accepted: 12/08/2023] [Indexed: 01/03/2024] Open
Abstract
Methylmercury (MeHg) is a potent toxin that exerts deleterious effects on human health via environmental contamination. Significant effects of MeHg on neuronal development in embryogenesis have been reported. Recently, our group demonstrated that MeHg exerts toxic effects on pre- and post-implantation embryonic development processes from zygote to blastocyst stage. Our results showed that MeHg impairs embryo development by induction of apoptosis through reactive oxygen species (ROS) generation that triggers caspase-3 cleavage and activation, which, in turn, stimulates p21-activated kinase 2 (PAK2) activity. Importantly, ROS were identified as a key upstream regulator of apoptotic events in MeHg-treated blastocysts. Data from the current study further confirmed that MeHg exerts hazardous effects on cell proliferation, apoptosis, implantation, and pre- and post-implantation embryo development. Notably, MeHg-induced injury was markedly prevented by co-culture with adipose-derived mesenchymal stem cells (ADMSCs) in vitro. Furthermore, ADMSC injection significantly reduced MeHg-mediated deleterious effects on embryo, placenta, and fetal development in vivo. Further investigation of the regulatory mechanisms by which co-cultured ADMSCs could prevent MeHg-induced impairment of embryo development revealed that ADMSCs effectively reduced ROS generation and its subsequent downstream apoptotic events, including loss of mitochondrial membrane potential and activation of caspase-3 and PAK2. The collective findings indicate that co-culture with mesenchymal stem cells (MSCs) or utilization of MSC-derived cell-conditioned medium offers an effective potential therapeutic strategy to prevent impairment of embryo development by MeHg.
Collapse
Affiliation(s)
- Cheng-Kai Lee
- Department of Obstetrics and Gynecology, Taoyuan General Hospital, Ministry of Health & Welfare, Zhongshan Road, Taoyuan District, Taoyuan City 33004, Taiwan
| | - Fu-Ting Wang
- Rehabilitation and Technical Aid Center, Taipei Veterans General Hospital, Section 2, Shipai Road, Beitou District, Taipei City 11217, Taiwan
| | - Chien-Hsun Huang
- Hungchi Gene IVF Center, Daxing West Road, Taoyuan District, Taoyuan City 330012, Taiwan
| | - Wen-Hsiung Chan
- Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Zhongbei Road, Zhongli District, Taoyuan City 32023, Taiwan
| |
Collapse
|
|
4
|
Chen HL, Peng K, Zeng DM, Yan J, Huang YQ, Jiang PY, Du YF, Ling X, Wu J. High-Salt Diet Aggravates Endothelial-to-Mesenchymal Transition in Glomerular Fibrosis in Dahl Salt-Sensitive Rats. Am J Hypertens 2023; 36:660-666. [PMID: 37179466 DOI: 10.1093/ajh/hpad048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/25/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Both diabetic and hypertensive nephropathy eventually progress to glomerulosclerosis. Previous studies revealed a potential role of endothelial-to-mesenchymal transition (EndMT) in the pathophysiology of glomerulosclerosis in diabetic rats. Therefore, we hypothesized that EndMT was also involved in the development of glomerulosclerosis in salt-sensitive hypertension. We aimed to explore the effects of high-salt diet on endothelial-to-mesenchymal transition (EndMT) in glomerulosclerosis in Dahl salt-sensitive (Dahl-SS) rats. METHODS Eight-week-old male rats were fed high-salt (8%NaCl; DSH group) or normal salt (0.3%NaCl; DSN group) for eight weeks, with systolic blood pressure (SBP), serum creatinine, urea, 24-hour urinary protein/sodium, renal interlobar artery blood flow, and pathological examination measured. We also examined endothelial-(CD31) and fibrosis-related protein(α-SMA) expressions in glomeruli. RESULTS High-salt diet increased SBP (DSH vs. DSN, 205.2 ± 8.9 vs. 135.4 ± 7.9 mm Hg, P < 0.01), 24-hour urinary protein (132.55 ± 11.75 vs. 23.52 ± 5.94 mg/day, P < 0.05), urine sodium excretions (14.09 ± 1.49 vs. 0.47 ± 0.06 mmol/day, P < 0.05), and renal interlobar artery resistance. Glomerulosclerosis increased (26.1 ± 4.6 vs. 7.3 ± 1.6%, P < 0.05), glomerular CD31 expressions decreased while α-SMA expression increased in DSH group. Immunofluorescence staining showed that CD31 and α-SMA co-expressed in glomeruli of the DSH group. The degree of glomerulosclerosis negatively correlated with CD31 expressions (r = -0.823, P < 0.01) but positively correlated with α-SMA expressions (r = 0.936, P < 0.01). CONCLUSIONS We demonstrated that a high-salt diet led to glomerulosclerosis involving the EndMT process, which played an essential role in glomerulosclerosis in hypertensive Dahl-SS rats.
Collapse
Affiliation(s)
- Hui-Lin Chen
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Kuang Peng
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Dian-Mei Zeng
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Jun Yan
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Ya-Qi Huang
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Pei-Yong Jiang
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Ya-Fang Du
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Xiang Ling
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| | - Jie Wu
- Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
| |
Collapse
|
|
5
|
Awadalla A, Hamam ET, Mostafa SA, Mahmoud SA, Elazab KM, El Nakib AM, Eldesoqui M, El-Sherbiny M, Ammar OA, Al-Serwi RH, Saleh MA, Sarhan A, Ali M. Hepatoprotective Effects of Hyaluronic Acid-Preconditioned Bone Marrow Mesenchymal Stem Cells against Liver Toxicity via the Inhibition of Apoptosis and the Wnt/β-Catenin Signaling Pathway. Cells 2023; 12:1526. [PMID: 37296647 PMCID: PMC10252276 DOI: 10.3390/cells12111526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/30/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Doxorubicin (DOX) is widely used to treat a variety of malignancies in both adults and children, including those of the bladder, breast, stomach, and ovaries. Despite this, it has been reported to cause hepatotoxicity. The recent discovery of bone marrow-derived mesenchymal stem cells' (BMSCs) therapeutic effects in the context of liver diseases suggests that their administration plays a part in the mitigation and rehabilitation of drug-induced toxicities. OBJECTIVES This study investigated whether bone BMSCs could reduce DOX-induced liver damage by blocking the Wnt/β-catenin pathway that causes fibrotic liver. MATERIALS AND METHODS BMSCs were isolated and treated with hyaluronic acid (HA) for 14 days before injection. Thirty-five mature male SD rats were categorized into four groups; group one (control) rats were supplemented with saline 0.9% for 28 days, group two (DOX) rats were injected with DOX (20 mg/kg), group three (DOX + BMSCs) rats were injected with 2 × 106 BMSCs after 4 days of DOX injection, group four (DOX + BMSCs + HA) rats were injected with 0.1 mL BMSCs pretreated with HA after 4 days of DOX. After 28 days the rats were sacrificed, and blood and liver tissue samples were subjected to biochemical and molecular analysis. Morphological and immunohistochemical observations were also carried out. RESULTS In terms of liver function and antioxidant findings, cells treated with HA showed considerable improvement compared to the DOX group (p < 0.05). Moreover, the expression of inflammatory markers (TGFβ1, iNos), apoptotic markers (Bax, Bcl2), cell tracking markers (SDF1α), fibrotic markers (β-catenin, Wnt7b, FN1, VEGF, and Col-1), and ROS markers (Nrf2, HO-1) was improved in BMSCs conditioned with HA in contrast to BMSCs alone (p < 0.05). CONCLUSION Our findings proved that BMSCs treated with HA exert their paracrine therapeutic effects via their secretome, suggesting that cell-based regenerative therapies conditioned with HA may be a viable alternative to reduce hepatotoxicity.
Collapse
Affiliation(s)
- Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Eman T. Hamam
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Sally Abdallah Mostafa
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Seham Ahmed Mahmoud
- Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| | - Khalid Mohamed Elazab
- Department of Biology, Faculty of Science, Jazan University, Jazan 82511, Saudi Arabia
| | - Ahmed Mohamed El Nakib
- Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mamdouh Eldesoqui
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Omar A. Ammar
- Basic Science Department, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - Rasha Hamed Al-Serwi
- Department of Basic Dental Sciences, College of Dentistry, Princess Nourahbint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - Mohamed A. Saleh
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Amira Sarhan
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed Ali
- Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
| |
Collapse
|
|
6
|
Ohtake T, Itaba S, Salybekov AA, Sheng Y, Sato T, Yanai M, Imagawa M, Fujii S, Kumagai H, Harata M, Asahara T, Kobayashi S. Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice. World J Stem Cells 2023; 15:268-280. [PMID: 37181001 PMCID: PMC10173816 DOI: 10.4252/wjsc.v15.i4.268] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/24/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD).
AIM To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice.
METHODS Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet.
RESULTS Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001).
CONCLUSION Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.
Collapse
Affiliation(s)
- Takayasu Ohtake
- Regenerative Medicine, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Shoichi Itaba
- Kamakura Techno-science Inc., Kamakura 248-0036, Japan
| | - Amankeldi A Salybekov
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Yin Sheng
- Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Tsutomu Sato
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Mitsuru Yanai
- Department of Pathology, Sapporo Tokushukai Hospital, Sapporo 004-0041, Japan
| | - Makoto Imagawa
- Department of Pathology, Sapporo Medical Center, Sapporo 004-0041, Japan
| | - Shigeo Fujii
- Kamakura Techno-science Inc., Kamakura 248-0036, Japan
| | | | | | - Takayuki Asahara
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
- Cell Processing and Cell/Genome Analysis Center, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Shuzo Kobayashi
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanazawa, Japan
| |
Collapse
|
|
7
|
Wu D, Liu J, Zhou C, Ma W, Zhou L, Ge Y, Jia R. Immunomagnetic Delivery of Adipose-Derived Endothelial Progenitor Cells for the Repair of Renal Ischemia-Reperfusion Injury in a Rat Model. Bioengineering (Basel) 2023; 10:bioengineering10050509. [PMID: 37237579 DOI: 10.3390/bioengineering10050509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
Renal ischemia-reperfusion injury (IRI) is a significant cause of acute kidney injury (AKI) and usually brings severe public health consequences. Adipose-derived endothelial progenitor cell (AdEPCs) transplantation is beneficial for AKI but suffers from low delivery efficiency. This study was conducted to explore the protective effects of magnetically delivered AdEPCs on the repair of renal IRI. Two types of magnetic delivery methods, namely the endocytosis magnetization (EM) method and the immunomagnetic (IM) method were fabricated using PEG@Fe3O4 and CD133@Fe3O4, and their cytotoxicities in AdEPCs were assessed. In the renal IRI rat model, magnetic AdEPCs were injected via the tail vein and a magnet was placed beside the injured kidney for magnetic guidance. The distribution of transplanted AdEPCs, renal function, and tubular damage were evaluated. Our results suggested that CD133@Fe3O4 had the minimum negative effects on the proliferation, apoptosis, angiogenesis, and migration of AdEPCs compared with PEG@Fe3O4. Renal magnetic guidance could significantly enhance the transplantation efficiency and the therapeutic outcomes of AdEPCs-PEG@Fe3O4 and AdEPCs-CD133@Fe3O4 in the injured kidneys. However, under renal magnetic guidance, AdEPCs-CD133@Fe3O4 had stronger therapeutic effects than PEG@Fe3O4 after renal IRI. The immunomagnetic delivery of AdEPCs with CD133@Fe3O4 could be a promising therapeutic strategy for renal IRI.
Collapse
Affiliation(s)
- Di Wu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Jingyu Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Wenjie Ma
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Liuhua Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Yuzheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| | - Ruipeng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China
| |
Collapse
|
|
8
|
Sueters J, Groenman FA, Bouman MB, Roovers JPW, de Vries R, Smit TH, Huirne JAF. Tissue Engineering Neovagina for Vaginoplasty in Mayer-Rokitansky-Küster-Hauser Syndrome and Gender Dysphoria Patients: A Systematic Review. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:28-46. [PMID: 35819292 DOI: 10.1089/ten.teb.2022.0067] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Background: Vaginoplasty is a surgical solution to multiple disorders, including Mayer-Rokitansky-Küster-Hauser syndrome and male-to-female gender dysphoria. Using nonvaginal tissues for these reconstructions is associated with many complications, and autologous vaginal tissue may not be sufficient. The potential of tissue engineering for vaginoplasty was studied through a systematic bibliography search. Cell types, biomaterials, and signaling factors were analyzed by investigating advantages, disadvantages, complications, and research quantity. Search Methods: A systematic search was performed in Medline, EMBASE, Web of Science, and Scopus until March 8, 2022. Term combinations for tissue engineering, guided tissue regeneration, regenerative medicine, and tissue scaffold were applied, together with vaginoplasty and neovagina. The snowball method was performed on references and a Google Scholar search on the first 200 hits. Original research articles on human and/or animal subjects that met the inclusion (reconstruction of vaginal tissue and tissue engineering method) and no exclusion criteria (not available as full text; written in foreign language; nonoriginal study article; genital surgery other than neovaginal reconstruction; and vaginal reconstruction with autologous or allogenic tissue without tissue engineering or scaffold) were assessed. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist, the Newcastle-Ottawa Scale, and the Gold Standard Publication Checklist were used to evaluate article quality and bias. Outcomes: A total of 31 out of 1569 articles were included. Data extraction was based on cell origin and type, biomaterial nature and composition, host species, number of hosts and controls, neovaginal size, replacement fraction, and signaling factors. An overview of used tissue engineering methods for neovaginal formation was created, showing high variance of cell types, biomaterials, and signaling factors and the same topics were rarely covered multiple times. Autologous vaginal cells and extracellular matrix-based biomaterials showed preferential properties, and stem cells carry potential. However, quality confirmation of orthotopic cell-seeded acellular vaginal matrix by clinical trials is needed as well as exploration of signaling factors for vaginoplasty. Impact statement General article quality was weak to sufficient due to unreported cofounders and incomplete animal study descriptions. Article quality and heterogenicity made identification of optimal cell types, biomaterials, or signaling factors unreliable. However, trends showed that autologous cells prevent complications and compatibility issues such as healthy cell destruction, whereas stem cells prevent cross talk (interference of signaling pathways by signals from other cell types) and rejection (but need confirmation testing beyond animal trials). Natural (orthotopic) extracellular matrix biomaterials have great preferential properties that encourage future research, and signaling factors for vascularization are important for tissue engineering of full-sized neovagina.
Collapse
Affiliation(s)
- Jayson Sueters
- Department of Gynaecology and Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Freek A Groenman
- Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Centre of Expertise on Gender Dysphoria, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Mark-Bram Bouman
- Centre of Expertise on Gender Dysphoria, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Department of Plastic, Reconstructive and Hand Surgery, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Jan Paul W Roovers
- Department of Obstetrics and Gynecology, Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands
| | - Ralph de Vries
- Medical Library, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Theo H Smit
- Department of Gynaecology and Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Department of Medical Biology, Amsterdam UMC location AMC, Amsterdam, The Netherlands
| | - Judith A F Huirne
- Department of Gynaecology and Amsterdam Reproduction and Development, Amsterdam UMC location VUmc, Amsterdam, The Netherlands.,Research Institute Reproduction and Development, Amsterdam UMC location AMC, Amsterdam, The Netherlands
| |
Collapse
|
|
9
|
Chen YT, Yang CC, Chiang JY, Sung PH, Shao PL, Huang CR, Lee MS, Yip HK. Prion Protein Overexpression in Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Effectively Protected Rodent Kidney Against Ischemia-Reperfusion Injury Via Enhancing ATP/Mitochondrial Biogenesis-Role of ADMSC Rejuvenation and Proliferation. Cell Transplant 2023; 32:9636897231211067. [PMID: 38078417 PMCID: PMC10714882 DOI: 10.1177/09636897231211067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 10/12/2023] [Accepted: 10/16/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND We tested the hypothesis that overexpression of cellular-prion-protein in adipose-derived mesenchymal stem cells (PrPCOE-ADMSCs) effectively protected the kidney against ischemia-reperfusion (IR) injury in rat. METHODS Part I of cell culture was categorized into A1(ADMSCs)/A2(ADMSCs+p-Cresol)/A3(PrPCOE in ADMSCs)/A4 (PrPCOE in ADMSCs+p-Cresol). Part II of cell culture was divided into B1(ADMSCs)/B2[ADMSCs+lipopolysaccharide (LPS)]/B3(PrPCOE in ADMSCs)/B4(PrPCOE in ADMSCs+LPS). Sprague-Dawley (SD) rats (n = 50) were equally categorized into groups 1 (sham-operated-control)/2 (IR)/3 (IR+ADMSCs/6.0 × 105 equally divided into bilateral-renal arteries and 6.0 × 105 intravenous administration by 1 h after IR)/4 [IR+PrPCOE-ADMSCs (identical dosage administered as group 3)]/5 [IR+silencing PRNP -ADMSCs (identical dosage administered as group 3)], and kidneys were harvested post-day 3 IR injury. RESULTS Part I results demonstrated that the cell viability at 24/48/72 h, BrdU uptake/number of mitDNA/APT concentration/mitochondrial-cytochrome-C+ cells and the protein expressions of ki67/PrPC at 72 h-cell culturing were significantly higher in PrPCOE-ADMSCs than in ADMSCs (all P < 0.001). The protein expressions of oxidative-stress (NOX-1/NOX2/NOX4/oxidized protein)/mitochondrial-damaged (p22-phox/cytosolic-cytochrome-C)/inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers were lowest in A1/A3 and significantly higher in A2 than in A4 (all P < 0.001). Part II result showed that the protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/IL-6)/apoptotic (cleaved caspase-3/cleaved-PARP) biomarkers exhibited an identical pattern of part I among the groups (all P < 0.001). The protein expressions of inflammatory (p-NF-κB/IL-1ß/TNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized-protein)/mitochondrial-damaged (cytosolic-cytochrome-C/p22-phox)/apoptotic (cleaved caspase-3/cleaved-PARP/mitochondrial-Bx)/autophagic (beclin-1/ratio of LC3B-II/LC3B-I)/fibrotic (Smad3/TGF-ß) biomarkers and kidney-injury-score/creatinine level were lowest in group 1, highest in group 2, significantly higher in group 5 than in groups 3/4 (all P < 0.0001). CONCLUSION PrPCOE in ADMSCs rejuvenated these cells and played a cardinal role on protecting the kidney against IR injury.
Collapse
Affiliation(s)
- Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung
| | - John Y. Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung
| | - Pei-Hsun Sung
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
| | - Pei-Lin Shao
- Department of Nursing, Asia University, Taichung
| | - Chi-Ruei Huang
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung
| | | | - Hon-Kan Yip
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung
- Department of Nursing, Asia University, Taichung
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan
| |
Collapse
|
|
10
|
Torrico S, Hotter G, Játiva S. Development of Cell Therapies for Renal Disease and Regenerative Medicine. Int J Mol Sci 2022; 23:ijms232415943. [PMID: 36555585 PMCID: PMC9783572 DOI: 10.3390/ijms232415943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/12/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022] Open
Abstract
The incidence of renal disease is gradually increasing worldwide, and this condition has become a major public health problem because it is a trigger for many other chronic diseases. Cell therapies using multipotent mesenchymal stromal cells, hematopoietic stem cells, macrophages, and other cell types have been used to induce regeneration and provide a cure for acute and chronic kidney disease in experimental models. This review describes the advances in cell therapy protocols applied to acute and chronic kidney injuries and the attempts to apply these treatments in a clinical setting.
Collapse
Affiliation(s)
- Selene Torrico
- M2rlab-XCELL, 28010 Madrid, Spain
- Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas Institut d’Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), 08036 Barcelona, Spain
- Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Georgina Hotter
- Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas Institut d’Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), 08036 Barcelona, Spain
- CIBER-BBN, Networking Center on Bioengineering, Biomaterials and Nanomedicine, 50018 Zaragoza, Spain
- Correspondence: (G.H.); (S.J.)
| | - Soraya Játiva
- M2rlab-XCELL, 28010 Madrid, Spain
- Department of Experimental Pathology, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Científicas Institut d’Investigacions Biomèdiques August Pi i Sunyer (IIBB-CSIC-IDIBAPS), 08036 Barcelona, Spain
- Correspondence: (G.H.); (S.J.)
| |
Collapse
|
|
11
|
Sung P, Yang C, Chiang JY, Chen C, Luo C, Yip H. Inhibition of histone methyltransferase G9a effectively protected the kidney against ischemia-reperfusion injury. Am J Transl Res 2022; 14:3683-3697. [PMID: 35836849 PMCID: PMC9274564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/30/2022] [Indexed: 06/15/2023]
Abstract
This study examined whether BIX01294, a histone methyltransferase G9a inhibitor, effectively preserves the renal function following acute kidney ischemia-reperfusion (AKIR) injury. Adult-male-SD rats (n = 24) were equally categorized into Group 1 (sham-operated control), Group 2 (AKIR + 1.0 cc N/S I.P. injection), and Group 3 (AKIR + BIX01294/5 mg/Kg by I.P. administration at 3 h after the procedure) and the kidneys were harvested at day-3 post-IR procedure. The results showed that by day 3, the levels of creatinine and the blood urea nitrogen (BUN) were significantly higher in group 3 and more significantly higher in group 2 than in group 1 (all P < 0.0001). The protein expression of upstream (TLR-2/TLR-4/MyD88/TRAF6/p-NF-κB) and downstream (IL-1ß/IL-6/TNF-α) inflammatory signaling molecules exhibited a pattern identical to that of creatinine levels among the groups (all P < 0.0001). The protein expression of oxidative stress (NOX-1/NOX-2), MAP kinase family members (ASK1/MKK4/MKK7/JNK/p-38/p-ERK1/2), apoptosis (cleaved-caspase3/cleaved-caspase8/cleaved-PARP/mitochondrial-Bax), fibrosis (Smad3/TGF-ß), and mitochondrial-damaged markers (cyclophilin D/cytosolic-cytochrome-C) displayed a pattern identical to that of creatinine levels among the groups (all P < 0.0001). The kidney injury score, fibrosis, cellular expression of inflammation (CD68+cells), and glomerulus/renal-tubular damaged markers (Snail/KIM-1/WT-1) exhibited an identical pattern, whereas the cellular expression of podocyte component (synaptopodin) displayed an opposite pattern of creatinine levels among the groups (all P < 0.0001). Therefore, the G9a inhibitor effectively protected kidneys against IR injury.
Collapse
Affiliation(s)
- Peihsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial HospitalKaohsiung, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial HospitalKaohsiung, Taiwan
| | - Chihchao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen UniversityKaohsiung, Taiwan
- Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical UniversityKaohsiung, Taiwan
| | - Chihhung Chen
- Divisions of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Chiwen Luo
- Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung, Taiwan
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung, Taiwan
| | - Honkan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial HospitalKaohsiung, Taiwan
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial HospitalKaohsiung, Taiwan
- School of Medicine, College of Medicine, Chang Gung UniversityTaoyuan, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical UniversityTaichung, Taiwan
- Department of Nursing, Asia UniversityTaichung, Taiwan
| |
Collapse
|
|
12
|
Chen K, Li Y, Xu L, Qian Y, Liu N, Zhou C, Liu J, Zhou L, Xu Z, Jia R, Ge YZ. Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment. Stem Cell Res Ther 2022; 13:238. [PMID: 35672766 PMCID: PMC9172199 DOI: 10.1186/s13287-022-02921-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/29/2022] [Indexed: 12/21/2022] Open
Abstract
Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.
Collapse
Affiliation(s)
- Ke Chen
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yang Li
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Luwei Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yiguan Qian
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ning Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Jingyu Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Liuhua Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Zheng Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ruipeng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
| | - Yu-Zheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
| |
Collapse
|
|
13
|
Tang W, Panja S, Jogdeo CM, Tang S, Ding L, Yu A, Foster KW, Dsouza DL, Chhonker YS, Jensen-Smith H, Jang HS, Boesen EI, Murry DJ, Padanilam B, Oupický D. Modified chitosan for effective renal delivery of siRNA to treat acute kidney injury. Biomaterials 2022; 285:121562. [PMID: 35552115 PMCID: PMC9133205 DOI: 10.1016/j.biomaterials.2022.121562] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 04/02/2022] [Accepted: 05/01/2022] [Indexed: 11/02/2022]
Abstract
Acute kidney injury (AKI) is characterized by a sudden decrease in renal function and impacts growing number of people worldwide. RNA interference (RNAi) showed potential to treat diseases with no or limited conventional therapies, including AKI. Suitable carriers are needed to protect and selectively deliver RNAi to target cells to fully explore this therapeutic modality. Here, we report on the synthesis of chitosan modified with α-cyclam-p-toluic acid (C-CS) as a novel siRNA carrier for targeted delivery to injured kidneys. We demonstrate that conjugation of the α-cyclam-p-toluic acid to chitosan imparts the C-CS polymer with targeting and antagonistic properties to cells overexpressing chemokine receptor CXCR4. In contrast, the parent α-cyclam-p-toluic acid showed no such properties. Self-assembled C-CS/siRNA nanoparticles rapidly accumulate in the injured kidneys and show long retention in renal tubules. Apoptosis and metabolic and inflammatory pathways induced by p53 are important pathological mechanisms in the development of AKI. Nanoparticles with siRNA against p53 (sip53) were formulated and intravenously injected for attenuation of IRI-AKI. Due to the favorable accumulation in injured kidneys, the treatment with C-CS/sip53 decreased renal injury, extent of renal apoptosis, macrophage and neutrophil infiltration, and improved renal function. Overall, our study suggests that C-CS/siRNA nanoparticles have the potential to effectively accumulate and deliver therapeutic siRNAs to injured kidneys through CXCR4 binding, providing a novel way for AKI therapy.
Collapse
Affiliation(s)
- Weimin Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sudipta Panja
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Chinmay M Jogdeo
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Siyuan Tang
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ling Ding
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ao Yu
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kirk W Foster
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Del L Dsouza
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Yashpal S Chhonker
- Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Heather Jensen-Smith
- Eppley Institute for Research in Cancer & Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Hee-Seong Jang
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Erika I Boesen
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Daryl J Murry
- Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Babu Padanilam
- Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - David Oupický
- Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
| |
Collapse
|
|
14
|
Awadalla A, Hussein AM, El-Far YM, El-Senduny FF, Barakat N, Hamam ET, Abdeen HM, El-Sherbiny M, Serria MS, Sarhan AA, Sena AM, Shokeir AA. Rapamycin Improves Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Renoprotective Effect against Cisplatin-Induced Acute Nephrotoxicity in Rats by Inhibiting the mTOR/AKT Signaling Pathway. Biomedicines 2022; 10:1295. [PMID: 35740317 PMCID: PMC9220220 DOI: 10.3390/biomedicines10061295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Because the poor survival of transplanted cells in a hostile microenvironment limits stem cell therapy, in the current study, we investigated the effect of rapamycin (Rapa)-preactivated autophagy on the survival and homing of transplanted adipose mesenchymal stem cells (ADMSCs) in a rat model of cisplatin (Cis)-induced nephrotoxicity, as well as the possible role of the mTOR/AKT signaling pathway. MATERIALS AND METHODS In vitro, ADMSCs isolated from rats were treated with 50 nmol/L rapamycin for 2 h, after which the cytoprotective and autophagy-inducing effects of Rapa were investigated. The cis-induced acute nephrotoxicity rat model was constructed in vivo. ADMSCs and Rapa-ADMSCs were administered into the tail vein before Cis therapy. At 3, 7, and 10 days after Cis injection, all animals were euthanized. The renal functions and morphology as well as autophagy response were assessed. RESULTS The pretreatment of cultured ADMSCs with Rapa caused a significant increase in autophagic activities and lysosome production of the cells, with a significant increase in the secretion of SDF-1, IL-10 and autophagy promoter LC3 and Beclin from these cells, while mTOR/AKT pathways were inhibited. In addition, the transplantation of Rapa-pretreated ADMSCs restored the kidney functions and morphology dramatically. Renal expression of SDF-1 and HIF1 was upregulated, while expression of IL-6, NF-kB and TGF-β1 was downregulated. CONCLUSIONS We concluded that the preactivation of autophagy with Rapa improves the survival and differentiation of the transplanted ADMSCs by inhibiting the mTOR/AKT signaling pathway, which in turn could significantly attenuate the Cis-induced acute renal injury.
Collapse
Affiliation(s)
- Amira Awadalla
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Abdelaziz M. Hussein
- Medical Physiology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Yousra M. El-Far
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Fardous F. El-Senduny
- Biochemistry Division, Chemistry Department, Faculty of Sciences, Mansoura University, Mansoura 35516, Egypt;
| | - Nashwa Barakat
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Eman T. Hamam
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Hanaa M. Abdeen
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; (H.M.A.); (M.S.S.)
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh 13713, Saudi Arabia;
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Mohamed S. Serria
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt; (H.M.A.); (M.S.S.)
| | - Amira A. Sarhan
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Asmaa M. Sena
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| | - Ahmed A. Shokeir
- Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt; (A.A.); (N.B.); (E.T.H.); (A.A.S.); (A.M.S.); (A.A.S.)
| |
Collapse
|
|
15
|
Du A, Liu D, Zhang W, Wang X, Chen S. Genipin-crosslinked decellularized scaffold induces regeneration of defective rat kidneys. J Biomater Appl 2022; 37:415-428. [DOI: 10.1177/08853282221104287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective: The purpose of this study was to improve the performance of decellularized renal scaffolds by the genipin crosslinking method to facilitate the regeneration of tissues and cells and provide better conditions for the regeneration and repair of defective kidneys. Methods: SD rats were randomly divided into three groups: normal group, uncrosslinked scaffold group and genipin-crosslinked scaffold group. Hematoxylin eosin, Masson and immunofluorescence staining was used to observe the histomorphological characteristics of the kidneys in each group. The preservation of the renal vascular structure in the three groups was observed by vascular casting. A collagenase degradation assay was used to detect the antidegradation ability of the kidney in the three groups. CCK8 assays were used to test the in vitro biocompatibility of the scaffolds. The lower 1/3 of the rat left kidney was excised, and the defect was filled with decellularized renal scaffolds to observe the effect of scaffold implantation on the regenerative ability of the defective kidney. Results: Histological images showed that the genipin-crosslinked scaffold did not destroy the structure of the scaffold, and the collagen fibers in the scaffold was more regular, and the outline of the glomerulus was clearer than uncrosslinked scaffold. The results of casting showed that the vascular structure of genipin-crosslinked scaffold was still intact. The anti-degradation ability test showed that the anti-degradation ability of genipin-crosslinked scaffold was significantly higher than that of the uncrosslinked scaffold. Cell culture experiments showed that the genipin-crosslinked scaffold had no cytotoxicity and promoted cell proliferation to some extent. In vivo scaffold transplantation experiments further demonstrated that the genipin-crosslinked scaffold had better anti-degradation and anti-inflammatory ability. Conclusion: Genipin-crosslinked rat kidney scaffold complemented kidney defects in rats can enhance scaffold-induced kidney regeneration and repair.
Collapse
Affiliation(s)
- Aoling Du
- School of Basic Medicine, Hubei University of Arts and Science, Xiangyang, China
- Institute of Clinical Anatomy & Reproductive Medicine, University of South China, Hengyang, Hunan, China
| | - Dan Liu
- School of Basic Medicine, Xiangnan University, Chenzhou, China
| | - Wenhui Zhang
- Institute of Clinical Anatomy & Reproductive Medicine, University of South China, Hengyang, Hunan, China
| | | | - Shenghua Chen
- Institute of Clinical Anatomy & Reproductive Medicine, University of South China, Hengyang, Hunan, China
| |
Collapse
|
|
16
|
Florentin J, O'Neil SP, Ohayon LL, Uddin A, Vasamsetti SB, Arunkumar A, Ghosh S, Boatz JC, Sui J, Kliment CR, Chan SY, Dutta P. VEGF Receptor 1 Promotes Hypoxia-Induced Hematopoietic Progenitor Proliferation and Differentiation. Front Immunol 2022; 13:882484. [PMID: 35634304 PMCID: PMC9133347 DOI: 10.3389/fimmu.2022.882484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/19/2022] [Indexed: 11/13/2022] Open
Abstract
Although it is well known that hypoxia incites unleashed cellular inflammation, the mechanisms of exaggerated cellular inflammation in hypoxic conditions are not known. We observed augmented proliferation of hematopoietic stem and progenitor cells (HSPC), precursors of inflammatory leukocytes, in mice under hypoxia. Consistently, a transcriptomic analysis of human HSPC exposed to hypoxic conditions revealed elevated expression of genes involved in progenitor proliferation and differentiation. Additionally, bone marrow cells in mice expressed high amount of vascular endothelial growth factor (VEGF), and HSPC elevated VEGF receptor 1 (VEGFr1) and its target genes in hypoxic conditions. In line with this, VEGFr1 blockade in vivo and in vitro decreased HSPC proliferation and attenuated inflammation. In silico and ChIP experiments demonstrated that HIF-1α binds to the promoter region of VEGFR1. Correspondingly, HIF1a silencing decreased VEGFr1 expression in HSPC and diminished their proliferation. These results indicate that VEGF signaling in HSPC is an important mediator of their proliferation and differentiation in hypoxia-induced inflammation and represents a potential therapeutic target to prevent aberrant inflammation in hypoxia-associated diseases.
Collapse
Affiliation(s)
- Jonathan Florentin
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Scott P O'Neil
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Lee L Ohayon
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Afaz Uddin
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Sathish Babu Vasamsetti
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Anagha Arunkumar
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Samit Ghosh
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Jennifer C Boatz
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Justin Sui
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Corrine R Kliment
- Department of Medicine, Division of Pulmonary and Critical Care, University of Pittsburgh, Pittsburgh, PA, United States
| | - Stephen Y Chan
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Partha Dutta
- Division of Cardiology, Department of Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| |
Collapse
|
|
17
|
Comparison of Stromal Vascular Fraction and Adipose-Derived Stem Cells for Protection of Renal Function in a Rodent Model of Ischemic Acute Kidney Injury. Stem Cells Int 2022; 2022:1379680. [PMID: 35578662 PMCID: PMC9107055 DOI: 10.1155/2022/1379680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 04/06/2022] [Accepted: 04/13/2022] [Indexed: 11/17/2022] Open
Abstract
Aims Few studies have compared the use of different cell types derived from adipose tissue or the optimal route for efficient and safe cell delivery in ischemic acute kidney injury (AKI). We compared the abilities of stromal vascular fraction (SVF) and adipose-derived stem cells (ADSC), injected via three different routes, to protect renal function in a rodent model of ischemic AKI. Methods Ninety male Sprague-Dawley rats were randomly divided into 9 groups: sham, nephrectomy control, AKI control, transaortic renal arterial SVF injection, renal parenchymal SVF injection, tail venous SVF injection, transaortic renal arterial ADSC injection, renal parenchymal ADSC injection, and tail venous ADSC injection groups. Their renal function was assessed 4 days before and 1, 2, 3, 4, 7, and 14 days after surgical procedures to induce ischemic AKI. The histomorphometric studies were performed 14 days after surgical procedures. Results Renal parenchymal injection of SVF notably reduced the level of serum blood urea nitrogen and creatinine elevation compared to the AKI control group. Renal parenchymal injection of SVF notably reduced the level of creatinine clearance decrease. In addition, collagen content was lower in the renal parenchymal SVF injection group, and fibrosis was reduced. Apoptosis was reduced in the renal parenchymal SVF injection group, and proliferation was increased. The expression levels of antioxidative markers such as glutathione reductase and peroxidase were higher in the renal parenchymal SVF injection group. Conclusions Our findings suggest that renal function is protected from ischemic AKI through renal parenchymal injection of SVF, which has enhanced antifibrotic, antiapoptotic, and antioxidative effects.
Collapse
|
|
18
|
Xu Z, Wang C, He Y, Mao X, Zhang MZ, Hou YP, Li B. Hypoxia-Inducible Factor Protects Against Acute Kidney Injury via the Wnt/β-Catenin Signaling Pathway. Am J Physiol Renal Physiol 2022; 322:F611-F624. [PMID: 35403451 DOI: 10.1152/ajprenal.00023.2022] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Promoting adaptive repair (AR) in acute kidney injury (AKI) is an effective strategy to preventprogression from AKI to chronic kidney disease (CKD). However, the mechanisms involved in renal repair after AKI remain unclear. In this study, we investigated the role of hypoxia-inducible factor (HIF), an important regulator of ischemic and hypoxic injury, in AKI during the repair phase. We established mouse models of ischemia-reperfusion injury (IRI)-induced AKI with AR or maladaptive repair (MAR). We found that after injury, the activation of HIF in the AR group was rapid, while in the MAR group, HIF activation was relatively delayed, and its expression was significantly lower than that in the AR group during the early repair phase. To further investigate the mechanism of HIF, we regulated the expression of HIF-1α and HIF-2α in HK-2 cells and EA.hy926 cells, respectively. Silencing HIF expression reduced proliferation and increased apoptosis in cells injured by hypoxia/reoxygenation (H/R). Self-healing ability was further reduced due to the downregulation of HIF. Moreover, HIF overexpression had the opposite effect. HIF increased the expression of β-catenin and its downstream target genes. Activation of Wnt/β-catenin by the small molecule activator SKL2001 mitigated the damaging effect of HIF knockdown, while blocking β-catenin with the inhibitor IWR-1-endo reduced the protective effects of HIF. In conclusion, HIF, which is highly expressed in the early stage after AKI, promotes renal repair by interacting with the Wnt/β-catenin signaling pathway.
Collapse
Affiliation(s)
- ZhiHui Xu
- Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chang Wang
- Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China
| | - YiXin He
- Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - XinYue Mao
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Man-Zhu Zhang
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Yan-Pei Hou
- Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bing Li
- Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.,Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China
| |
Collapse
|
|
19
|
Liu J, Li Y, Lyu L, Xiao L, Memon AA, Yu X, Halim A, Patel S, Osman A, Yin W, Jiang J, Naini S, Lim K, Zhang A, Williams JD, Koester R, Qi KZ, Fucci QA, Ding L, Chang S, Patel A, Mori Y, Chaudhari A, Bao A, Liu J, Lu TS, Siedlecki A. Integrin α5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells. J Am Soc Nephrol 2022; 33:565-582. [PMID: 35091451 PMCID: PMC8975065 DOI: 10.1681/asn.2021020140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 12/27/2021] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND Endothelial cell injury is a common nidus of renal injury in patients and consistent with the high prevalence of AKI reported during the coronavirus disease 2019 pandemic. This cell type expresses integrin α5 (ITGA5), which is essential to the Tie2 signaling pathway. The microRNA miR-218-5p is upregulated in endothelial progenitor cells (EPCs) after hypoxia, but microRNA regulation of Tie2 in the EPC lineage is unclear. METHODS We isolated human kidney-derived EPCs (hkEPCs) and surveyed microRNA target transcripts. A preclinical model of ischemic kidney injury was used to evaluate the effect of hkEPCs on capillary repair. We used a genetic knockout model to evaluate the effect of deleting endogenous expression of miR-218 specifically in angioblasts. RESULTS After ischemic in vitro preconditioning, miR-218-5p was elevated in hkEPCs. We found miR-218-5p bound to ITGA5 mRNA transcript and decreased ITGA5 protein expression. Phosphorylation of 42/44 MAPK decreased by 73.6% in hkEPCs treated with miR-218-5p. Cells supplemented with miR-218-5p downregulated ITGA5 synthesis and decreased 42/44 MAPK phosphorylation. In a CD309-Cre/miR-218-2-LoxP mammalian model (a conditional knockout mouse model designed to delete pre-miR-218-2 exclusively in CD309+ cells), homozygotes at e18.5 contained avascular glomeruli, whereas heterozygote adults showed susceptibility to kidney injury. Isolated EPCs from the mouse kidney contained high amounts of ITGA5 and showed decreased migratory capacity in three-dimensional cell culture. CONCLUSIONS These results demonstrate the critical regulatory role of miR-218-5p in kidney EPC migration, a finding that may inform efforts to treat microvascular kidney injury via therapeutic cell delivery.
Collapse
Affiliation(s)
- Jialing Liu
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts,Nephrology, Department of Medicine, Guangzhou University of Chinese Medicine, The Second Affiliated Hospital of Chinese Medicine, Guangzhou, China
| | - Yi Li
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Lingna Lyu
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts,Department of Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Liang Xiao
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts,Department of Surgery and Oncology, Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China
| | - Aliza A. Memon
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Xin Yu
- Blood Transfusion Research Institute, Wuxi Red Cross Blood Center, Wuxi, Jiangsu, China
| | - Arvin Halim
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Shivani Patel
- Division of Nephrology, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts
| | | | - Wenqing Yin
- Division of Nephrology, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts
| | - Jie Jiang
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts,Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
| | - Said Naini
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kenneth Lim
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Aifeng Zhang
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jonathan D. Williams
- DNA Identification Testing Division, Laboratory Corporation of America Holdings, Burlington, North Carolina
| | - Ruth Koester
- DNA Identification Testing Division, Laboratory Corporation of America Holdings, Burlington, North Carolina
| | | | - Quynh-Anh Fucci
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Lai Ding
- Program for Interdisciplinary Neuroscience, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Steven Chang
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ankit Patel
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yutaro Mori
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Advika Chaudhari
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Aaron Bao
- Washington University in St. Louis, St. Louis, Missouri
| | - Jia Liu
- Shenzhen Jiake Biotechnology, Shenzhen, China
| | - Tzong-Shi Lu
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew Siedlecki
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
20
|
Cheng L, Yang X, Jian Y, Liu J, Ke X, Chen S, Yang D, Yang D. SIRT3 deficiency exacerbates early-stage fibrosis after ischaemia-reperfusion-induced AKI. Cell Signal 2022; 93:110284. [PMID: 35182747 DOI: 10.1016/j.cellsig.2022.110284] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 02/08/2022] [Accepted: 02/14/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND Sirtuin 3 (SIRT3) is a crucial regulator of mitochondrial function and is associated with injury and repair in acute kidney injury (AKI). To investigate whether mitochondrial damage and early renal fibrosis are associated with decreased renal SIRT3 levels, we established an in vivo model. METHODS In vivo, we established ischaemia-reperfusion-induced AKI (IR-AKI) models in wild-type (WT) and SIRT3-knockout (SIRT3-KO) mice. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured by an automatic biochemical analyser, and renal pathological changes were examined by haematoxylin and eosin (HE) staining. Renal fibrosis in mice was assessed by Masson's trichrome staining. The expression of SIRT3, renal fibrosis-related markers (FN and α-SMA), and mitochondrial markers (DRP1, FIS1, OPA1, and MFN1) was measured by Western blotting. Morphological changes in mitochondria in renal tubular epithelial cells were analysed by transmission electron microscopy (TEM). RESULTS The levels of Scr and BUN were elevated with severe renal pathological damage in the IR-AKI model, especially in SIRT3-KO mice. In the IR-AKI model, the obvious increases in FN and α-SMA protein levels suggested that there was severe fibrosis in the kidney tissue, OPA1 and MFN1 protein levels were reduced while DRP1 and FIS1 protein levels were greatly increased. TEM photomicrographs showed that mitochondrial fragmentation was increased in the renal tubular epithelial cells of mice with IR injury. SIRT3-KO mice exhibited exacerbated changes. CONCLUSION Our findings indicate that SIRT3 plays a significant role in early-stage fibrosis after IR-AKI by regulating mitochondrial dynamics and that SIRT3 deficiency exacerbates renal dysfunction and renal fibrosis.
Collapse
Affiliation(s)
- Lingli Cheng
- Department of Nephrology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, No. 99 Zhangzhidong Road (formerly Ziyang Road), Wuchang District, Wuhan, Hubei 430060, China
| | - Xueyan Yang
- Department of Nephrology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, No. 99 Zhangzhidong Road (formerly Ziyang Road), Wuchang District, Wuhan, Hubei 430060, China
| | - Yonghong Jian
- Department of Nephrology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, No. 99 Zhangzhidong Road (formerly Ziyang Road), Wuchang District, Wuhan, Hubei 430060, China
| | - Jie Liu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Jianghan District, Wuhan, Hubei 430022, China
| | - Xinyu Ke
- Department of Nephrology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, No. 99 Zhangzhidong Road (formerly Ziyang Road), Wuchang District, Wuhan, Hubei 430060, China
| | - Sha Chen
- Department of Nephrology, Tianjin Hospital, No. 406 Jiefang South Road, Hexi District, Tianjin 300211, China
| | - Dingwei Yang
- Department of Nephrology, Tianjin Hospital, No. 406 Jiefang South Road, Hexi District, Tianjin 300211, China.
| | - Dingping Yang
- Department of Nephrology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, No. 99 Zhangzhidong Road (formerly Ziyang Road), Wuchang District, Wuhan, Hubei 430060, China.
| |
Collapse
|
|
21
|
Molecular Mechanisms of Kidney Injury and Repair. Int J Mol Sci 2022; 23:ijms23031542. [PMID: 35163470 PMCID: PMC8835923 DOI: 10.3390/ijms23031542] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/17/2022] Open
Abstract
Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance.
Collapse
|
|
22
|
Lee MS, Yip HK, Yang CC, Chiang JY, Huang TH, Li YC, Chen KH, Sung PH. Overexpression of miR-19a and miR-20a in iPS-MSCs preserves renal function of chronic kidney disease with acute ischaemia-reperfusion injury in rat. J Cell Mol Med 2021; 25:7675-7689. [PMID: 34161651 PMCID: PMC8358869 DOI: 10.1111/jcmm.16613] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 04/19/2021] [Accepted: 04/23/2021] [Indexed: 12/29/2022] Open
Abstract
This study tested the hypothesis that therapy with double overexpression of miR‐19a‐3p and miR‐20a‐5p (miRDOE) to human inducible pluripotent stem cell–derived mesenchymal stem cells (iPS‐MSCs) was superior to iPS‐MSCs alone for preserving renal function in rat with pre‐existing chronic kidney disease (CKD), followed by ischaemia‐reperfusion (IR) injury. In vitro study demonstrated that the protein expressions of oxidative stress (NOX‐1/NOX‐2/NOX4/oxidized protein/p22phox), inflammatory downstream signalling (TLR2&4/MyD88/TRAF6/IKK‐ß/p‐NFκB/IL‐1ß/IL‐6/MMP‐9) and cell apoptosis/death signalling (cleaved caspase‐3/mitochondrial Bax/p‐ERKs/p‐JNK/p‐p38) at time‐points of 24‐hour/48‐hour cell cultures were significantly increased in p‐Cresol‐treated NRK‐52E cells than in the control that was significantly reversed by miR‐19a‐3p‐transfected iPS‐MSC (all P < .001). Animals were categorized into group 1 (sham‐operated control), group 2 (CKD‐IR), group 3 (CKD‐IR + oligo‐miRDOE of iPS‐MSCs/6.0 ×105/intra‐renal artery transfusion/3 hours after IR procedure), group 4 (CKD‐IR + iPS‐MSCs) and group 5 (CKD‐IR + miRDOE of iPS‐MSCs/6.0 ×105/intra‐renal artery transfusion/3 hour after IR procedure). By day 35, the creatinine/BUN levels were lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3 and 4 (all P < .0001) but they showed no difference between the latter two groups. The protein expressions of oxidative stress, inflammatory downstream signalling and cell apoptosis/death signalling exhibited an identical pattern of creatinine level among the five groups (all P < .00001). Also, the microscopic findings demonstrated that the kidney injury score/fibrotic area/number of inflammatory cells (CD14+/CD68+) exhibited an identical pattern of creatine level (all P < .0001). The miRDOE of iPS‐MSCs was superior to iPS‐MSCs for preserving the residual kidney function and architecture in CKD‐IR rat.
Collapse
Affiliation(s)
- Mel S Lee
- Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, China
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Tien-Hung Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yi-Chen Li
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| |
Collapse
|
|
23
|
Huang J, Kong Y, Xie C, Zhou L. Stem/progenitor cell in kidney: characteristics, homing, coordination, and maintenance. Stem Cell Res Ther 2021; 12:197. [PMID: 33743826 PMCID: PMC7981824 DOI: 10.1186/s13287-021-02266-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Renal failure has a high prevalence and is becoming a public health problem worldwide. However, the renal replacement therapies such as dialysis are not yet satisfactory for its multiple complications. While stem/progenitor cell-mediated tissue repair and regenerative medicine show there is light at the end of tunnel. Hence, a better understanding of the characteristics of stem/progenitor cells in kidney and their homing capacity would greatly promote the development of stem cell research and therapy in the kidney field and open a new route to explore new strategies of kidney protection. In this review, we generally summarize the main stem/progenitor cells derived from kidney in situ or originating from the circulation, especially bone marrow. We also elaborate on the kidney-specific microenvironment that allows stem/progenitor cell growth and chemotaxis, and comment on their interaction. Finally, we highlight potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy. Our review provides important clues to better understand and control the growth of stem cells in kidneys and develop new therapeutic strategies.
Collapse
Affiliation(s)
- Jiewu Huang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China
| | - Yaozhong Kong
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Chao Xie
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China. .,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
| |
Collapse
|
|
24
|
Peritubular Capillary Rarefaction: An Underappreciated Regulator of CKD Progression. Int J Mol Sci 2020; 21:ijms21218255. [PMID: 33158122 PMCID: PMC7662781 DOI: 10.3390/ijms21218255] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 10/29/2020] [Indexed: 12/15/2022] Open
Abstract
Peritubular capillary (PTC) rarefaction is commonly detected in chronic kidney disease (CKD) such as hypertensive nephrosclerosis and diabetic nephropathy. Moreover, PTC rarefaction prominently correlates with impaired kidney function and predicts the future development of end-stage renal disease in patients with CKD. However, it is still underappreciated that PTC rarefaction is a pivotal regulator of CKD progression, primarily because the molecular mechanisms of PTC rarefaction have not been well-elucidated. In addition to the established mechanisms (reduced proangiogenic factors and increased anti-angiogenic factors), recent studies discovered significant contribution of the following elements to PTC loss: (1) prompt susceptibility of PTC to injury, (2) impaired proliferation of PTC, (3) apoptosis/senescence of PTC, and (4) pericyte detachment from PTC. Mainly based on the recent and novel findings in basic research and clinical study, this review describes the roles of the above-mentioned elements in PTC loss and focuses on the major factors regulating PTC angiogenesis, the assessment of PTC rarefaction and its surrogate markers, and an overview of the possible therapeutic agents to mitigate PTC rarefaction during CKD progression. PTC rarefaction is not only a prominent histological characteristic of CKD but also a central driving force of CKD progression.
Collapse
|
|
25
|
Erythropoietin Preconditioning Mobilizes Endothelial Progenitor Cells to Attenuate Nephron-Sparing Surgery-Induced Ischemia-Reperfusion Injury. Transplant Proc 2020; 52:2955-2963. [PMID: 32703672 DOI: 10.1016/j.transproceed.2020.05.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 04/17/2020] [Accepted: 05/12/2020] [Indexed: 11/22/2022]
Abstract
The purpose of this study was to examine the role of endothelial progenitor cells (EPCs) in protection against ischemic-reperfusion injury (IRI) in a nephron-sparing surgery (NSS) rat model using erythropoietin (EPO) preconditioning. Fifty-four male Sprague-Dawley rats were randomly divided into 3 groups for right kidney nephrectomy treatment: sham group (exposure without clamp treatment), NSS group (3 days of peritoneal phosphate buffered saline [PBS] injection before renal blood vessels were clamped for 40 mins and NSS was performed), and EPO group (3 days of EPO abdomen injections prior to renal blood vessel clamping for 40 min before NSS was performed). After 12, 24, and 72 hours, inferior vena cava blood and renal tissues were harvested. The extent of renal injury was assessed, along with EPC number, cell proliferation, angiogenesis, and vascular growth factor expression. EPO preconditioning significantly improved renal function and histologic morphology, indicated by reduced blood urea nitrogen (BUN) ([33.12 ± 1.88] vs [16.03 ± 0.91], P < .05) and serum creatinine (Scr) ([190.2 ± 20.23] vs [77.23 ± 5.82], P < .05) levels and histologic injury scores ([3.20 ± 0.78] vs [1.70 ± 0.67], P < .05). Angiogenesis in peritubular capillaries markedly increased in the EPO group. EPC numbers increased in the kidneys at 24 hours following reperfusion in the EPO group, compared to the NSS group. Furthermore, EPO preconditioning also increased SDF-1α and CXCR7 expression at 24 hours following reperfusion relative to the NSS group. These findings suggest that EPO pretreatment can reduce renal injury in rats caused by IRI. Mechanistically, this may be related to EPC mobilization and recruitment to injured renal tissues by SDF-1α and CXCR7.
Collapse
|
|
26
|
Lin KC, Chen KH, Wallace CG, Chen YL, Ko SF, Lee MS, Yip HK. Combined Therapy With Hyperbaric Oxygen and Melatonin Effectively Reduce Brain Infarct Volume and Preserve Neurological Function After Acute Ischemic Infarct in Rat. J Neuropathol Exp Neurol 2020; 78:949-960. [PMID: 31504676 DOI: 10.1093/jnen/nlz076] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
This study tested the hypothesis that combined hyperbaric oxygen (HBO) and melatonin (Mel) was superior to either one for protecting the brain functional and parenchymal integrity from acute ischemic stroke (IS) injury. Adult-male Sprague-Dawley rats were divided into groups 1 (sham-operated control), 2 (IS), 3 (IS + HBO), 4 (IS + Mel), and 5 (IS + HBO-Mel). By day 28 after IS, the brain infarct area (BIA) was lowest in group 1, highest in group 2, significantly higher in groups 3 and 4 than in group 5, but not different between groups 3 and 4. The neurological function at day 7, 14, and 28 exhibited an opposite pattern to BIA among the 5 groups. The protein expressions of inflammatory (IL-1β/IL-6/iNOS/TNF-α/p-NF-κB), apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial Bax), mitochondrial/DNA-damaged (cytochrome-C/γ-H2AX), oxidative stress (NOX-1/NOX-2), and autophagy (i.e. ratio of CL3B-II/CL3B-I) biomarkers displayed an identical pattern of BIA among 5 groups. Cellular expressions of inflammation (F4/80+/GFAP+) and DNA-damaged biomarker (γ-H2AX+) exhibited an identical pattern, whereas the integrities of myelin sheath/neuron (MPB+/NeuN+), endothelial cell (CD31+/vWF+), and number of small vessels exhibited an opposite pattern of BIA among the 5 groups. Combined HBO-Mel therapy offered an additional benefit in protecting the brain against IS injury.
Collapse
Affiliation(s)
- Kun-Chen Lin
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | - Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine
- Institute for Translational Research in Biomedicine
| | | | - Mel S Lee
- Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine
- Institute for Translational Research in Biomedicine
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University
- Department of Nursing, Asia University, Taichung, Taiwan
| |
Collapse
|
|
27
|
Wilson MR, Holladay J, Sheridan R, Hostetter G, Berghuis B, Graveel C, Essenburg C, Peck A, Ho TH, Stanton M, Chandler RL. Lgr5-positive endothelial progenitor cells occupy a tumor and injury prone niche in the kidney vasa recta. Stem Cell Res 2020; 46:101849. [PMID: 32464345 DOI: 10.1016/j.scr.2020.101849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 02/13/2020] [Accepted: 05/12/2020] [Indexed: 01/10/2023] Open
Abstract
The Wnt pathway co-receptor, Leucine Rich Repeat Containing G Protein-Coupled Receptor 5 (LGR5), labels tumor-prone stem cell populations in certain types of tissue. In this study, we show that ARID1A and PIK3CA mutations in LGR5+ cells result in renal angiosarcomas in adult mice. The tumors originate in the renal medulla. We further show that LGR5 labels SOX17+/CD31+/CD34+/CD133+/AQP1+/CD146+ endothelial progenitor cells within the descending vasa recta or straight arterioles of the kidney, which are specialized capillaries that maintain medullary osmotic gradients necessary for water reabsorption and the production of concentrated urine. LGR5+ endothelial progenitor cells are tightly associated with contractile pericytes within the descending vasa recta. Long-term in vivo lineage tracing revealed that LGR5+ cells give rise to renal medullary vasculature. We further show that LGR5+ cells are activated in response to ischemic kidney injury. Our findings uncover a physiologically relevant endothelial progenitor cell population within the kidney vasa recta.
Collapse
Affiliation(s)
- Mike R Wilson
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Jeanne Holladay
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA
| | - Rachael Sheridan
- Flow Cytometry Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Galen Hostetter
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Bree Berghuis
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Carrie Graveel
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Curt Essenburg
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Anderson Peck
- Small Animal Imaging Facility, Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | - Thai H Ho
- Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
| | - Melissa Stanton
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Ronald L Chandler
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI 49503, USA; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Women's Health, Spectrum Health System, Grand Rapids, MI 49341, USA.
| |
Collapse
|
|
28
|
Imafuku A, Oka M, Miyabe Y, Sekiya S, Nitta K, Shimizu T. Rat Mesenchymal Stromal Cell Sheets Suppress Renal Fibrosis via Microvascular Protection. Stem Cells Transl Med 2019; 8:1330-1341. [PMID: 31675167 PMCID: PMC6877761 DOI: 10.1002/sctm.19-0113] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 09/04/2019] [Indexed: 12/13/2022] Open
Abstract
Renal fibrosis is one of the largest global health care problems, and microvascular (MV) injury is important in the development of progressive fibrosis. Although conventional cell therapy suppresses kidney injury via the role of vasoprotective cytokines, the effects are limited due to low retention of administered cells. We recently described that transplantation of hepatocyte growth factor (HGF)‐transgenic mesothelial cell sheets showed a remarkable cell survival and strong therapeutic effects in a rat renal fibrosis model. Due to the translational hurdles of transgenic cells, we here applied this technique for allogeneic transplantation using rat bone marrow mesenchymal stromal cells (MSCs). MSC sheets were transplanted onto the kidney surface of a rat renal ischemia–reperfusion‐injury model and the effects were compared between those in untreated rats and those receiving intravenous (IV) administration of the cells. We found that donor‐cell survival was superior in the cell sheet group relative to the IV group, and that the cell sheets secreted HGF and vascular endothelial growth factor (VEGF) up to day 14. Transplantation of cell sheets increased the expression of activated HGF/VEGF receptors in the kidney. There was no evidence of migration of transplanted cells into the kidney parenchyma. Additionally, the cell sheets significantly suppressed renal dysfunction, MV injury, and fibrosis as compared with that observed in the untreated and IV groups. Furthermore, we demonstrated that the MSC sheet protected MV density in the whole kidney according to three‐dimensional microcomputed tomography. In conclusion, MSC sheets strongly prevented renal fibrosis via MV protection, suggesting that this strategy represents a potential novel therapy for various kidney diseases. stem cells translational medicine2019;8:1330&1341 Rat bone marrow mesenchymal stromal cell sheets were transplanted onto the kidney surface. In ischemia–reperfusion‐injury, microvascular density loss caused by endothelial injury resulted in progressive renal fibrosis. Mesenchymal stromal cell sheets remained long‐term on the kidney surface and protected the microvasculature, which resulted in suppression of progressive fibrosis. The therapeutic effects were partially explained by the role of hepatocyte growth factor/vascular endothelial growth factor secreted from mesenchymal stromal cell sheets.![]()
Collapse
Affiliation(s)
- Aya Imafuku
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Masatoshi Oka
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan.,Cell Sheet Tissue Engineering Center (CSTEC), Department of Pharmaceutics and Pharmaceutical Chemistry, Health Sciences, University of Utah, Salt Lake City, Utah, USA
| | - Yoei Miyabe
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Sachiko Sekiya
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Kosaku Nitta
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| |
Collapse
|
|
29
|
Chen YT, Yang CC, Lin KC, Chen KH, Sung PH, Shao PL, Li YC, Chiang JY, Yip HK. Preactivated and disaggregated shape-changed platelets protect kidney against from ischemia-reperfusion injury in rat through attenuating inflammation reaction. J Tissue Eng Regen Med 2019; 13:2155-2168. [PMID: 31502757 DOI: 10.1002/term.2960] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/29/2019] [Accepted: 09/03/2019] [Indexed: 12/27/2022]
Abstract
This study tested the hypothesis that preactivated and disaggregated shape-changed platelet (PreD-SCP) therapy significantly protected rat kidney from ischemia-reperfusion (IR) injury. Adult-male Sprague-Dawley rats (n = 24) were equally categorized into Groups 1 (sham-operated control [SC]), 2 (SC + PreD-SCP), 3 (IR only), and 4 (IR + PreD-SCP). By 72 hr after IR procedure, the circulatory levels of creatinine, blood urine nitrogen and inflammatory biomarkers (interleukin [IL]-6/tumor necrosis factor [TNF]-α), and ratio of urine protein to urine creatinine were significantly higher in Group 3 than in other groups and significantly higher in Group 4 than in Groups 1 and 2, but they showed no different between Groups 1 and 2 (all p < .001). The microscopic findings showed that the expressions of kidney injury score, cellular inflammation (MMP-9/CD14//F4/80), and fibrotic area were identical to the circulatory inflammation, whereas the integrity of podocyte components (ZO-1/synaptopodin/podocin) exhibited an opposite to circulatory inflammation among the four groups (all p < .0001). The protein expressions of inflammatory (TNF-α/IL-1ß/NF-κB/iNOS/TRAF6/MyD88/TLR-4), apoptotic/cell death (mitochondrial Bax/cleaved caspase-3/p-53), oxidized protein, mitogen-activated protein kinase family (p-38/p-JNK/p-c-JUN), and mitochondrial-damaged biomarkers displayed a similar pattern, whereas the antiapoptotic (Bcl-2/Bcl-XL) and integrity of mitochondrial biomarkers followed an opposite trend to circulatory inflammation among the four groups (all p < .001). PreD-SCP therapy effectively protected the kidney against IR injury.
Collapse
Affiliation(s)
- Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kun-Chen Lin
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Lin Shao
- Department of Nursing, Asia University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Yi-Chen Li
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Hon-Kan Yip
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| |
Collapse
|
|
30
|
Francis WR, Ireland RE, Spear AM, Jenner D, Watts SA, Kirkman E, Pallister I. Flow Cytometric Analysis of Hematopoietic Populations in Rat Bone Marrow. Impact of Trauma and Hemorrhagic Shock. Cytometry A 2019; 95:1167-1177. [PMID: 31595661 PMCID: PMC6900111 DOI: 10.1002/cyto.a.23903] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 08/19/2019] [Accepted: 09/13/2019] [Indexed: 12/20/2022]
Abstract
Severe injury and hemorrhagic shock (HS) result in multiple changes to hematopoietic differentiation, which contribute to the development of immunosuppression and multiple organ failure (MOF). Understanding the changes that take place during the acute injury phase may help predict which patients will develop MOF and provide potential targets for therapy. Obtaining bone marrow from humans during the acute injury phase is difficult so published data are largely derived from peripheral blood samples, which infer bone marrow changes that reflect the sustained inflammatory response. This preliminary and opportunistic study investigated leucopoietic changes in rat bone marrow 6 h following traumatic injury and HS. Terminally anesthetized male Porton Wistar rats were allocated randomly to receive a sham operation (cannulation with no injury) or femoral fracture and HS. Bone marrow cells were flushed from rat femurs and immunophenotypically stained with specific antibody panels for lymphoid (CD45R, CD127, CD90, and IgM) or myeloid (CD11b, CD45, and RP-1) lineages. Subsequently, cell populations were fluorescence-activated cell sorted for morphological assessment. Stage-specific cell populations were identified using a limited number of antibodies, and leucopoietic changes were determined 6 h following trauma and HS. Myeloid subpopulations could be identified by varying levels CD11b expression, CD45, and RP-1. Trauma and HS resulted in a significant reduction in total CD11b + myeloid cells including both immature (RP-1(-)) and mature (RP-1+) granulocytes. Multiple B-cell lymphoid subsets were identified. The total percentage of CD90+ subsets remained unchanged following trauma and HS, but there was a reduction in the numbers of maturing CD90(-) cells suggesting movement into the periphery. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.
Collapse
Affiliation(s)
| | - Rachel E Ireland
- Defence Science and Technology Laboratory, Porton Down, England, UK
| | - Abigail M Spear
- Defence Science and Technology Laboratory, Porton Down, England, UK
| | - Dominic Jenner
- Defence Science and Technology Laboratory, Porton Down, England, UK
| | - Sarah A Watts
- Defence Science and Technology Laboratory, Porton Down, England, UK
| | - Emrys Kirkman
- Defence Science and Technology Laboratory, Porton Down, England, UK
| | - Ian Pallister
- Institute of Life Science, Swansea University, Wales, UK.,Department of Trauma & Orthopaedics, Morriston Hospital, Swansea, Wales, UK
| |
Collapse
|
|
31
|
Xing L, Song EL, Jia XB, Ma J, Li B, Gao X. Nephroprotective effect of losartan in IgA model rat. J Int Med Res 2019; 47:5205-5215. [PMID: 31638466 PMCID: PMC6997782 DOI: 10.1177/0300060519871865] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 08/01/2019] [Indexed: 11/15/2022] Open
Abstract
Objective This study was performed to investigate the possible nephroprotective effects of losartan in a rat model of experimental IgA nephropathy (IgAN). Methods Thirty male Sprague–Dawley rats were randomly divided into three groups. The rats in the model group were treated with bovine serum albumin (oral gavage), lipopolysaccharide (tail vein injection), and carbon tetrachloride (subcutaneous injection); rats in the losartan group received treatments similar to those of the model group, and were orally gavaged with losartan; and rats in the control group received phosphate-buffered saline alone (both orally and intravenously). Results Losartan treatment lowered the 24-hour urinary protein, serum blood urea nitrogen, and serum creatinine levels. Proliferating mesangial cells with a variable increase in the mesangial matrix were detected in the model group, whereas injury in the losartan group was significantly attenuated. Immunohistochemistry revealed that the expression levels of transforming growth factor (TGF)-β1 and α-smooth muscle actin were significantly elevated in the model group but reduced in the losartan group. The expression levels of TGF-β1 and monocyte chemoattractant protein-1 were minimal in the control group, significantly increased in the model group, and reduced in the losartan group. Conclusion Losartan has a protective effect against tubulointerstitial injury in IgAN.
Collapse
Affiliation(s)
- Li Xing
- Department of Nephrology, First Affiliated Hospital of Harbin
Medical University, Harbin, P. R. China
| | - Er Lin Song
- Department of Urinary Surgery, First Affiliated Hospital of
Harbin Medical University, Harbin, P. R. China
| | - Xi Bei Jia
- Department of Nephrology, First Affiliated Hospital of Harbin
Medical University, Harbin, P. R. China
| | - Jing Ma
- Department of Nephrology, First Affiliated Hospital of Harbin
Medical University, Harbin, P. R. China
| | - Bing Li
- Department of Nephrology, Second Affiliated Hospital of Harbin
Medical University, Harbin, P. R. China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology of Harbin
Medical University, Harbin, P. R. China
| |
Collapse
|
|
32
|
Kamel NM, Abd El Fattah MA, El-Abhar HS, Abdallah DM. Novel repair mechanisms in a renal ischaemia/reperfusion model: Subsequent saxagliptin treatment modulates the pro-angiogenic GLP-1/cAMP/VEGF, ANP/eNOS/NO, SDF-1α/CXCR4, and Kim-1/STAT3/HIF-1α/VEGF/eNOS pathways. Eur J Pharmacol 2019; 861:172620. [PMID: 31437429 DOI: 10.1016/j.ejphar.2019.172620] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 08/09/2019] [Accepted: 08/19/2019] [Indexed: 12/21/2022]
Abstract
The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30 mg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.
Collapse
Affiliation(s)
- Nada M Kamel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Mai A Abd El Fattah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Hanan S El-Abhar
- Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt.
| | - Dalaal M Abdallah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| |
Collapse
|
|
33
|
Sun IO, Santelli A, Abumoawad A, Eirin A, Ferguson CM, Woollard JR, Lerman A, Textor SC, Puranik AS, Lerman LO. Loss of Renal Peritubular Capillaries in Hypertensive Patients Is Detectable by Urinary Endothelial Microparticle Levels. Hypertension 2019; 72:1180-1188. [PMID: 30354805 DOI: 10.1161/hypertensionaha.118.11766] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hypertension, an important cause of chronic kidney disease, is characterized by peritubular capillary (PTC) loss. Circulating levels of endothelial microparticles (EMPs) reflect systemic endothelial injury. We hypothesized that systemic and urinary PTC-EMPs levels would reflect renal microvascular injury in hypertensive patients. We prospectively measured by flow cytometry renal vein, inferior vena cava, and urinary levels of EMPs in essential (n=14) and renovascular (RVH; n=24) hypertensive patients and compared them with peripheral blood and urinary levels in healthy volunteers (n=14). PTC-EMPs were identified as urinary exosomes positive for the PTC marker plasmalemmal-vesicle-associated protein. In 7 RVH patients, PTC and fibrosis were also quantified in renal biopsy, and in 18 RVH patients, PTC-EMPs were measured again 3 months after continued medical therapy with or without stenting (n=9 each). Renal vein and systemic PTC-EMPs levels were not different among the groups, whereas their urinary levels were elevated in both RVH and essential hypertension versus healthy volunteers (56.8%±12.7% and 62.8%±10.7% versus 34.0%±17.8%; both P≤0.001). Urinary PTC-EMPs levels correlated directly with blood pressure and inversely with estimated glomerular filtration rate. Furthermore, in RVH, urinary PTC-EMPs levels correlated directly with stenotic kidney hypoxia, histological PTC count, and fibrosis and inversely with cortical perfusion. Three months after treatment, the change in urinary PTC-EMPs levels correlated inversely with a change in renal function ( r=-0.582; P=0.011). Therefore, urinary PTC-EMPs levels are increased in hypertensive patients and may reflect renal microcirculation injury, whereas systemic PTC-EMPs levels are unchanged. Urinary PTC-EMPs may be useful as novel biomarkers of intrarenal capillary loss.
Collapse
Affiliation(s)
- In O Sun
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.).,Division of Nephrology, Department of Internal Medicine, Presbyterian Medical Center, Jeonju, Korea (I.O.S.)
| | - Adrian Santelli
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - Abdelrhman Abumoawad
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - Alfonso Eirin
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - Christopher M Ferguson
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - John R Woollard
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (A.L.)
| | - Stephen C Textor
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - Amrutesh S Puranik
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| | - Lilach O Lerman
- From the Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN (I.O.S., A.S., A.A., A.E., C.M.F., J.R.W., S.C.T., A.S.P., L.O.L.)
| |
Collapse
|
|
34
|
Zhao L, Hu C, Zhang P, Jiang H, Chen J. Genetic communication by extracellular vesicles is an important mechanism underlying stem cell-based therapy-mediated protection against acute kidney injury. Stem Cell Res Ther 2019; 10:119. [PMID: 30995947 PMCID: PMC6471862 DOI: 10.1186/s13287-019-1227-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Stem cell-based therapy appears to be a promising new candidate for acute kidney injury (AKI) management. Traditionally, it has been accepted that the mechanism underlying the regenerative effect of stem cells is based on their paracrine/endocrine activity, including release of bioactive factors that act on injured renal cells and presentation of proangiogenic, antiapoptotic, antioxidative, and immunomodulatory effects. Recently, multiple studies have confirmed that extracellular vesicles (EVs) are a kind of vesicle rich in a broad variety of biologically active molecules, including lipids, proteins, and, in particular, nucleic acids. EVs are able to transfer genetic information to target cells, alter target gene regulatory networks, and exert biological effects. Stem cell-derived EVs (SC-EVs) are emerging as potent genetic information sources that deliver mRNAs and miRNAs to injured renal cells and exert renoprotective effects during AKI. On the other hand, EVs originating from injured renal cells also contain genetic information that is believed to be able to influence phenotypic and functional changes in stem cells, favoring renal recovery. In this review, we summarize studies providing evidence of genetic communication during the application of stem cells in preclinical AKI models, aiming to clarify the mechanism and describe the therapeutic effects of stem cell-based therapy in AKI patients.
Collapse
Affiliation(s)
- Lingfei Zhao
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Chenxia Hu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Ping Zhang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Hua Jiang
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Jianghua Chen
- Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China. .,Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang Province, People's Republic of China. .,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
| |
Collapse
|
|
35
|
Chou YH, Liao FL, Chen YT, Yeh PY, Liu CH, Shih HM, Chang FC, Chiang WC, Chu TS, Lin SL. Erythropoietin modulates macrophages but not post-ischemic acute kidney injury in mice. J Formos Med Assoc 2019; 118:494-503. [DOI: 10.1016/j.jfma.2018.10.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Revised: 10/09/2018] [Accepted: 10/23/2018] [Indexed: 01/11/2023] Open
|
|
36
|
Shen WC, Chou YH, Huang HP, Sheen JF, Hung SC, Chen HF. Induced pluripotent stem cell-derived endothelial progenitor cells attenuate ischemic acute kidney injury and cardiac dysfunction. Stem Cell Res Ther 2018; 9:344. [PMID: 30526689 PMCID: PMC6288873 DOI: 10.1186/s13287-018-1092-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/31/2018] [Accepted: 11/26/2018] [Indexed: 12/18/2022] Open
Abstract
Background Renal ischemia–reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), which is associated with high morbidity and mortality. AKI is a serious and costly medical condition. Effective therapy for AKI is an unmet clinical need, and molecular mechanisms underlying the interactions between an injured kidney and distant organs remain unclear. Therefore, novel therapeutic strategies should be developed. Methods We directed the differentiation of human induced pluripotent stem (iPS) cells into endothelial progenitor cells (iEPCs), which were then applied for treating mouse AKI. The mouse model of AKI was induced by I/R injury. Results We discovered that intravenously infused iEPCs were recruited to the injured kidney, expressed the mature endothelial cell marker CD31, and replaced injured endothelial cells. Moreover, infused iEPCs produced abundant proangiogenic proteins, which entered into circulation. In AKI mice, blood urea nitrogen and plasma creatinine levels increased 2 days after I/R injury and reduced after the infusion of iEPCs. Tubular injury, cell apoptosis, and peritubular capillary rarefaction in injured kidneys were attenuated accordingly. In the AKI mice, iEPC therapy also ameliorated apoptosis of cardiomyocytes and cardiac dysfunction, as indicated by echocardiography. The therapy also ameliorated an increase in serum brain natriuretic peptide. Regarding the relevant mechanisms, indoxyl sulfate and interleukin-1β synergistically induced apoptosis of cardiomyocytes. Systemic iEPC therapy downregulated the proapoptotic protein caspase-3 and upregulated the anti-apoptotic protein Bcl-2 in the hearts of the AKI mice, possibly through the reduction of indoxyl sulfate and interleukin-1β. Conclusions Therapy using human iPS cell-derived iEPCs provided a protective effect against ischemic AKI and remote cardiac dysfunction through the repair of endothelial cells and the attenuation of cardiomyocyte apoptosis. Electronic supplementary material The online version of this article (10.1186/s13287-018-1092-x) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Wen-Ching Shen
- Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.,Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yu-Hsiang Chou
- Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.,Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Renal Division, Department of Internal Medicine, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan
| | - Hsiang-Po Huang
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.,Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Jenn-Feng Sheen
- Department of Biotechnology, National Formosa University, Yun-Lin, Taiwan
| | - Shih-Chieh Hung
- Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan.,Integrative Stem Cell Center, Department of Orthopaedics, China Medical University Hospital, Taichung, 404, Taiwan.,Institute of Biomedical Sciences, Academia Sinica, Taipei, 105, Taiwan
| | - Hsin-Fu Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan. .,Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
| |
Collapse
|
|
37
|
Xing L, Song E, Yu CY, Jia XB, Ma J, Sui MS, Wang MA, Gao X. Bone marrow–derived mesenchymal stem cells attenuate tubulointerstitial injury through multiple mechanisms in UUO model. J Cell Biochem 2018; 120:9737-9746. [PMID: 30525227 DOI: 10.1002/jcb.28254] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 10/24/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Li Xing
- Department of Nephrology First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Erlin Song
- Department of Urinary Surgery First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Cheng Yuan Yu
- Department of cadre First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Xi Bei Jia
- Department of Nephrology First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Jing Ma
- Department of Nephrology First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Man Shu Sui
- Department of Nephrology First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Ming Ao Wang
- Department of Nephrology First Affiliated Hospital of Harbin Medical University Harbin Heilongjiang China
| | - Xu Gao
- Department of Biochemistry and Molecular Biology Harbin Medical University Harbin Heilongjiang China
| |
Collapse
|
|
38
|
Jang MJ, You D, Park JY, Kim K, Aum J, Lee C, Song G, Shin HC, Suh N, Kim YM, Kim CS. Hypoxic Preconditioned Mesenchymal Stromal Cell Therapy in a Rat Model of Renal Ischemia-reperfusion Injury: Development of Optimal Protocol to Potentiate Therapeutic Efficacy. Int J Stem Cells 2018; 11:157-167. [PMID: 30497128 PMCID: PMC6285294 DOI: 10.15283/ijsc18073] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 08/28/2018] [Accepted: 10/12/2018] [Indexed: 12/18/2022] Open
Abstract
Although previous and ongoing clinical studies have used stromal cells during renal ischemia-reperfusion injury (IRI), there is little consensus regarding the optimal protocol. We aimed to optimize the protocol for hypoxic preconditioned human bone marrow-derived mesenchymal stromal cell (HP-hBMSC) therapy in a rat model of renal IRI. We determined the optimal injection route (renal arterial, renal parenchymal, and tail venous injection), dose (low-dose: 1×106, moderate-dose: 2×106, and high-dose: 4×106), and injection period (pre-, concurrent-, and post-IRI). During optimal injection route study, renal arterial injections significantly reduced the decreasing glomerular filtration rate (GFR), as compared to GFRs for the IRI control group, 2 and 4 days after IRI. Therapeutic effects and histological recoveries were the greatest in the group receiving renal arterial injections. During the dose finding study, high-dose injections significantly reduced the decreasing GFR, as compared to GFRs for the IRI control group, 3 days after IRI. Therapeutic effects and histological recoveries were the greatest in the high-dose injection group. While determining the optimal injection timing study, concurrent-IRI injection reduced elevated serum creatinine levels, as compared to those of the IRI control group, 1 day after IRI. Pre-IRI injection significantly reduced the decreasing GFR, as compared with GFRs for the IRI control group, 1 day after IRI. Therapeutic effects and histological recoveries were the greatest in the concurrent-IRI group. In conclusion, the concurrent-IRI administration of a high dose of HP-hBMSC via the renal artery leads to an optimal recovery of renal function after renal IRI.
Collapse
Affiliation(s)
- Myoung Jin Jang
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dalsan You
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Young Park
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Kim
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joomin Aum
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chunwoo Lee
- Department of Urology, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, Korea
| | - Geehyun Song
- Department of Urology, Kangwon National University Hospital, Chuncheon, Korea
| | | | - Nayoung Suh
- Department of Pharmaceutical Engineering, College of Medical Sciences, Soon Chun Hyang University, Asan, Korea
| | | | - Choung-Soo Kim
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| |
Collapse
|
|
39
|
Zhang Y, Zhu Z, Hua K, Yao L, Liu Y, Ding J. Umbilical cord-derived mesenchymal stem cell transplantation in vaginal replacement in vitro and in a rat model. Am J Transl Res 2018; 10:3762-3772. [PMID: 30662626 PMCID: PMC6291690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 10/16/2018] [Indexed: 06/09/2023]
Abstract
Cell transplantation strategies represent a potential therapeutic approach towards repair of congenital vaginal agenesis. In this study, the efficacy and mechanisms of action of treatment with human umbilical cord-derived mesenchymal stem cells (UC-MSCs) on vaginal regeneration was explored. UC-MSC transplantation alone, small intestinal submucosal (SIS) grafting alone, and a combination of UC-MSC transplantation/SIS grafting were performed with a vaginal defect rat model. Histological analyses of tissue sections were subsequently performed. UC-MSCs promoted the recovery of keratinizing squamous epithelium and papillae to nearly the same levels as in normal tissue. Of the treatments tested, UC-MSC transplantation showed optimal performance in inhibiting collagen deposition and accelerating the synthesis of elastin to maintain tissue elasticity. UC-MSC treatment also increased Cyclin D1, Ki67, and CD31 expression as assessed by immunohistochemistry. We also investigated the effects of UC-MSC secretions on keratinocytes in a co-culture model. UC-MSCs significantly stimulated vaginal tissue repair by promoting vaginal epithelium regeneration via paracrine factors but not by exploiting their keratinocyte differentiation potential. Further, UC-MSCs facilitated epithelial cell viability and promoted cell cycle progression via the AKT/GSK3β/Cyclin D1 pathway. These results indicate that UC-MSC transplantation is a feasible approach for vaginal tissue regeneration.
Collapse
Affiliation(s)
- Yiqun Zhang
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan UniversityShanghai, P. R. China
- Shanghai Medical College, Fudan UniversityShanghai, P. R. China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan UniversityShanghai, P. R. China
| | - Zhongyi Zhu
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan UniversityShanghai, P. R. China
- Shanghai Medical College, Fudan UniversityShanghai, P. R. China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan UniversityShanghai, P. R. China
| | - Keqin Hua
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan UniversityShanghai, P. R. China
- Shanghai Medical College, Fudan UniversityShanghai, P. R. China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan UniversityShanghai, P. R. China
| | - Liangqing Yao
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan UniversityShanghai, P. R. China
- Shanghai Medical College, Fudan UniversityShanghai, P. R. China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan UniversityShanghai, P. R. China
| | - Yongjun Liu
- Alliancells Institute of Stem Cells and Translational Regenerative MedicineTianjin 300308, P. R. China
| | - Jingxin Ding
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan UniversityShanghai, P. R. China
- Shanghai Medical College, Fudan UniversityShanghai, P. R. China
- Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan UniversityShanghai, P. R. China
| |
Collapse
|
|
40
|
Ohtake T, Kobayashi S, Slavin S, Mochida Y, Ishioka K, Moriya H, Hidaka S, Matsuura R, Sumida M, Katagiri D, Noiri E, Okada K, Mizuno H, Tanaka R. Human Peripheral Blood Mononuclear Cells Incubated in Vasculogenic Conditioning Medium Dramatically Improve Ischemia/Reperfusion Acute Kidney Injury in Mice. Cell Transplant 2018; 27:520-530. [PMID: 29737200 PMCID: PMC6038042 DOI: 10.1177/0963689717753186] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Acute kidney injury (AKI) is a major clinical problem that still has no established treatment. We investigated the efficacy of cultured human peripheral blood mononuclear cells (PBMNCs) for AKI. Ischemia/reperfusion injury (IRI) was used to induce AKI in male nonobese diabetic (NOD/severe combined immunodeficiency) mice aged 7 to 8 wk. PBMNCs were isolated from healthy volunteers and were subjected to quality and quantity controlled (QQc) culture for 7 d in medium containing stem cell factor, thrombopoietin, Flt-3 ligand, vascular endothelial growth factor, and interleukin 6. IRI-induced mice were divided into 3 groups and administered (1) 1 × 106 PBMNCs after QQc culture (QQc PBMNCs group), (2) 1 × 106 PBMNCs without QQc culture (non-QQc PBMNCs group), or (3) vehicle without PBMNCs (IRI control group). PBMNCs were injected via the tail vein 24 h after induction of IRI, followed by assessment of renal function, histological changes, and homing of injected cells. Blood urea nitrogen and serum creatinine (Cr) 72 h after induction of IRI in the QQc PBMNCs group dramatically improved compared with those in the IRI control and the non-QQc PBMNCs groups, accompanied by the improvement of tubular damages. Interstitial fibrosis 14 d after induction of IRI was also significantly improved in the QQc PBMNCs group compared with the other groups. The renoprotective effect noted in the QQc PBMNCs group was accompanied by reduction of peritubular capillary loss. The change of PBMNCs’ population (increase of CD34+ cells, CD133+ cells, and CD206+ cells) and increased endothelial progenitor cell colony-forming potential by QQc culture might be one of the beneficial mechanisms for restoring AKI. In conclusion, an injection of human QQc PBMNCs 24 h after induction of IRI dramatically improved AKI in mice.
Collapse
Affiliation(s)
- Takayasu Ohtake
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.,2 Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Shuzo Kobayashi
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.,2 Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan
| | | | - Yasuhiro Mochida
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Kunihiro Ishioka
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Hidekazu Moriya
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Sumi Hidaka
- 1 Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Ryo Matsuura
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Maki Sumida
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Daisuke Katagiri
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Eisei Noiri
- 4 Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
| | - Kayoko Okada
- 5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan
| | - Hiroshi Mizuno
- 5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan
| | - Rica Tanaka
- 5 Department of Plastic and Reconstructive Surgery, Juntendo University School of Medicine, Ochanomizu, Japan
| |
Collapse
|
|
41
|
Zhao H, Alam A, Soo AP, George AJT, Ma D. Ischemia-Reperfusion Injury Reduces Long Term Renal Graft Survival: Mechanism and Beyond. EBioMedicine 2018; 28:31-42. [PMID: 29398595 PMCID: PMC5835570 DOI: 10.1016/j.ebiom.2018.01.025] [Citation(s) in RCA: 218] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 01/18/2018] [Accepted: 01/20/2018] [Indexed: 01/10/2023] Open
Abstract
Ischemia-reperfusion injury (IRI) during renal transplantation often initiates non-specific inflammatory responses that can result in the loss of kidney graft viability. However, the long-term consequence of IRI on renal grafts survival is uncertain. Here we review clinical evidence and laboratory studies, and elucidate the association between early IRI and later graft loss. Our critical analysis of previous publications indicates that early IRI does contribute to later graft loss through reduction of renal functional mass, graft vascular injury, and chronic hypoxia, as well as subsequent fibrosis. IRI is also known to induce kidney allograft dysfunction and acute rejection, reducing graft survival. Therefore, attempts have been made to substitute traditional preserving solutions with novel agents, yielding promising results.
Ischaemia reperfusion injury (IRI) potentiates delayed renal graft function and causes reduction in renal graft survival IRI causes innate immune system activation, hypoxic injury, inflammation and graft vascular disease Reducing prolonged cold ischaemic time improves graft survival Novel protective strategies include mesenchymal stem cells, machine perfusion, and ex vivo preservation solution saturated with gas. Further studies are needed to investigate the long-term effects of novel ex vivo preservation agents
Collapse
Affiliation(s)
- Hailin Zhao
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | - Azeem Alam
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | - Aurelie Pac Soo
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK
| | | | - Daqing Ma
- Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
| |
Collapse
|
|
42
|
Basile DP, Collett JA, Yoder MC. Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury. Acta Physiol (Oxf) 2018; 222:10.1111/apha.12914. [PMID: 28656611 PMCID: PMC5745310 DOI: 10.1111/apha.12914] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 05/10/2017] [Accepted: 06/21/2017] [Indexed: 12/12/2022]
Abstract
Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as 'endothelial progenitor' that may mediate vascular repair such as pro-angiogenic cells and endothelial colony-forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre-clinical studies.
Collapse
Affiliation(s)
- David P. Basile
- Department of Cellular & Integrative Physiology, Indiana University School of Medicine
| | - Jason A. Collett
- Department of Cellular & Integrative Physiology, Indiana University School of Medicine
| | - Mervin C. Yoder
- Department of Pediatrics, Indiana University School of Medicine
| |
Collapse
|
|
43
|
Zhen YY, Yang CC, Hung CC, Lee CC, Lee CC, Wu CH, Chen YT, Chen WY, Chen KH, Yip HK, Ko SF. Extendin-4 protects kidney from acute ischemia-reperfusion injury through upregulation of NRF2 signaling. Am J Transl Res 2017; 9:4756-4771. [PMID: 29218078 PMCID: PMC5714764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Accepted: 10/16/2017] [Indexed: 06/07/2023]
Abstract
This study tested the hypothesis that exendin-4 (Ex4) protects kidneys against ischemia-reperfusion (IR) injury mainly through upregulation of nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling and downregulation of oxidative stress. Male-adult Sprague-Dawley rats (n=24) were equally divided into group 1 (sham-operated control), group 2 [IR only, ischemia (1 h)/reperfusion (72 h)] and group 3 (IR-Ex4, 10 μg/kg at 30 min, 24 h, 48 h after IR procedure). The in vitro study demonstrated that the protein expressions of phosphorylated (p)-Akt and Nrf2 were significantly progressively increased at time points of 0/0.5/1/3 h and 0/0.5/1/3/6/12/24 h, respectively in NRK-52E cells co-cultured with Ex4 (20 nM) (all P<0.0001). Additionally, the protein expressions of NOX-1/NOX2 were significantly increased, whereas p-Akt was significantly decreased in NRK-52E cells co-cultured with P-cresol (200 μM) that were significantly reversed after Ex4 treatment (all P<0.0001). As compared with baseline, the creatinine level, left/right kidney weight and MCP-1-positively stained area in the kidney parenchyma were significantly increased at 24 h after the IR procedure and significantly progressively decreased after that (all P<0.0001). By 27 h after IR, creatinine level/MCP-1 + area was significantly higher in group 2 than in groups 1 and 3, and significantly higher in group 3 than in group 1 (all P<0.0001). The numbers of Nrf2 +/NQO-1 + cells/SOD activity in kidney parenchyma were significantly lower in group 2 than in groups 1 and 3, and significantly lower in group 1 than in group 3 (all P<0.0001). In conclusion, Ex4 protected kidney from IR injury through upregulating antioxidants and downregulating inflammation/oxidative stress.
Collapse
Affiliation(s)
- Yen-Yi Zhen
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung, Taiwan
- Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Chi-Chih Hung
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical UniversityKaohsiung, Taiwan
| | - Chia-Chang Lee
- Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
- Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 833, Taiwan
| | - Chen-Chang Lee
- Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 833, Taiwan
| | - Chien-Hsing Wu
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Yen-Ta Chen
- Divisions of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Wei-Yu Chen
- Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 83301, Taiwan
| | - Hon-Kan Yip
- Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
- Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical UniversityTaichung 40402, Taiwan
- Department of Nursing, Asia UniversityTaichung 41354, Taiwan, China
| | - Sheung-Fat Ko
- Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung 833, Taiwan
| |
Collapse
|
|
44
|
Tsou LK, Huang YH, Song JS, Ke YY, Huang JK, Shia KS. Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology. Med Res Rev 2017; 38:1188-1234. [PMID: 28768055 DOI: 10.1002/med.21464] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 07/13/2017] [Accepted: 07/16/2017] [Indexed: 12/12/2022]
Abstract
CXCR4 antagonists (e.g., PlerixaforTM ) have been successfully validated as stem cell mobilizers for peripheral blood stem cell transplantation. Applications of the CXCR4 antagonists have heralded the era of cell-based therapy and opened a potential therapeutic horizon for many unmet medical needs such as kidney injury, ischemic stroke, cancer, and myocardial infarction. In this review, we first introduce the central role of CXCR4 in diverse cellular signaling pathways and discuss its involvement in several disease progressions. We then highlight the molecular design and optimization strategies for targeting CXCR4 from a large number of case studies, concluding that polyamines are the preferred CXCR4-binding ligands compared to other structural options, presumably by mimicking the highly positively charged natural ligand CXCL12. These results could be further justified with computer-aided docking into the CXCR4 crystal structure wherein both major and minor subpockets of the binding cavity are considered functionally important. Finally, from the clinical point of view, CXCR4 antagonists could mobilize hematopoietic stem/progenitor cells with long-term repopulating capacity to the peripheral blood, promising to replace surgically obtained bone marrow cells as a preferred source for stem cell transplantation.
Collapse
Affiliation(s)
- Lun Kelvin Tsou
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | | | - Jen-Shin Song
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | - Yi-Yu Ke
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | - Jing-Kai Huang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| | - Kak-Shan Shia
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, Taiwan, ROC
| |
Collapse
|
|
45
|
Dang LTH, Aburatani T, Marsh GA, Johnson BG, Alimperti S, Yoon CJ, Huang A, Szak S, Nakagawa N, Gomez I, Ren S, Read SK, Sparages C, Aplin AC, Nicosia RF, Chen C, Ligresti G, Duffield JS. Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury. Biomaterials 2017; 141:314-329. [PMID: 28711779 DOI: 10.1016/j.biomaterials.2017.07.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 06/07/2017] [Accepted: 07/06/2017] [Indexed: 02/06/2023]
Abstract
Loss of the microvascular (MV) network results in tissue ischemia, loss of tissue function, and is a hallmark of chronic diseases. The incorporation of a functional vascular network with that of the host remains a challenge to utilizing engineered tissues in clinically relevant therapies. We showed that vascular-bed-specific endothelial cells (ECs) exhibit differing angiogenic capacities, with kidney microvascular endothelial cells (MVECs) being the most deficient, and sought to explore the underlying mechanism. Constitutive activation of the phosphatase PTEN in kidney MVECs resulted in impaired PI3K/AKT activity in response to vascular endothelial growth factor (VEGF). Suppression of PTEN in vivo resulted in microvascular regeneration, but was insufficient to improve tissue function. Promoter analysis of the differentially regulated genes in KMVECs suggests that the transcription factor FOXO1 is highly active and RNAseq analysis revealed that hyperactive FOXO1 inhibits VEGF-Notch-dependent tip-cell formation by direct and indirect inhibition of DLL4 expression in response to VEGF. Inhibition of FOXO1 enhanced angiogenesis in human bio-engineered capillaries, and resulted in microvascular regeneration and improved function in mouse models of injury-repair.
Collapse
Affiliation(s)
- Lan T H Dang
- Research & Development, Biogen, Cambridge, MA, USA.
| | - Takahide Aburatani
- Division of Nephrology, Departments of Medicine & Pathology, University of Washington, Seattle, USA; Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA
| | | | | | | | | | - Angela Huang
- Research & Development, Biogen, Cambridge, MA, USA
| | - Suzanne Szak
- Research & Development, Biogen, Cambridge, MA, USA
| | - Naoki Nakagawa
- Division of Nephrology, Departments of Medicine & Pathology, University of Washington, Seattle, USA; Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA
| | - Ivan Gomez
- Research & Development, Biogen, Cambridge, MA, USA
| | - Shuyu Ren
- Research & Development, Biogen, Cambridge, MA, USA
| | - Sarah K Read
- Research & Development, Biogen, Cambridge, MA, USA
| | | | - Alfred C Aplin
- Department of Pathology, University of Washington, Seattle, WA, USA
| | - Roberto F Nicosia
- Department of Pathology, University of Washington, Seattle, WA, USA; Pathology and Laboratory Medicine Service, VA Puget Sound Health Care System, Seattle, WA, USA
| | - Chris Chen
- Department of Bioengineering, Boston University, Boston, USA
| | | | - Jeremy S Duffield
- Research & Development, Biogen, Cambridge, MA, USA; Division of Nephrology, Departments of Medicine & Pathology, University of Washington, Seattle, USA; Institute of Stem Cell & Regenerative Medicine, University of Washington, Seattle, WA, USA.
| |
Collapse
|
|
46
|
Chen YT, Wallace CG, Yang CC, Chen CH, Chen KH, Sung PH, Chen YL, Chai HT, Chung SY, Chua S, Lee FY, Ko SF, Lee MS, Yip HK. DPP-4 enzyme deficiency protects kidney from acute ischemia-reperfusion injury: role for remote intermittent bowel ischemia-reperfusion preconditioning. Oncotarget 2017; 8:54821-54837. [PMID: 28903385 PMCID: PMC5589624 DOI: 10.18632/oncotarget.18962] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 06/17/2017] [Indexed: 01/25/2023] Open
Abstract
We analyzed the effects of acute ischemia-reperfusion (KIR) injury on the status of kidney function and architecture in dipeptidyl peptidase4-difficient (DPP4D) rats and the effect of remote small bowel ischemia-reperfusion (BIR) preconditioning. DPP4-deficient (DPP4D) and normal Fischer344 (F344) rats were divided into 6 groups: (1) sham-F344, (2) sham-DPP4D, (3) KIR-F344 (4) KIR-DPP4D, (5) DPP4D-KIR-extendin-9-39 and (6) BIR-KIR-F344. Blood creatinine and urea nitrogen levels and the urinary protein-to-creatinine ratio was higher in KIR-F344 rats than BIR-KIR-F344 or KIR-DPP4D rats 72 h after acute KIR. Conversely, the circulating glucagon-like peptide 1 (GLP-1) levels were higher in BIR-KIR-F344 and KIR-DPP4D than KIR-F344 rats after acute KIR. KIR-F344 rats showed greater inflammation, oxidative stress, apoptosis, DNA damage and kidney injury than other rat groups. Damage to the kidney architecture in KIR-F344 rats was greater than in BIR-KIR-F344 or KIR-DPP4D rats. Expression of antioxidant proteins and GLP-1 receptor was higher in kidneys from KIR-DPP4D and BIR-KIR-F344 than KIR-F344 rats, which suggests better intrinsic responses. We therefore suggest that elevated circulating GLP-1 levels due to DPP4 deficiency and BIR preconditioning protect kidney function and architecture during acute IR injury.
Collapse
Affiliation(s)
- Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chih-Hung Chen
- Division of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuan-Hung Chen
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Yung-Lung Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Han-Tan Chai
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Ying Chung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sarah Chua
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Fan-Yen Lee
- Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheung-Fat Ko
- Department of Radiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Mel S Lee
- Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| |
Collapse
|
|
47
|
Destefani AC, Sirtoli GM, Nogueira BV. Advances in the Knowledge about Kidney Decellularization and Repopulation. Front Bioeng Biotechnol 2017; 5:34. [PMID: 28620603 PMCID: PMC5451511 DOI: 10.3389/fbioe.2017.00034] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 05/03/2017] [Indexed: 12/15/2022] Open
Abstract
End-stage renal disease (ESRD) is characterized by the progressive deterioration of renal function that may compromise different tissues and organs. The major treatment indicated for patients with ESRD is kidney transplantation. However, the shortage of available organs, as well as the high rate of organ rejection, supports the need for new therapies. Thus, the implementation of tissue bioengineering to organ regeneration has emerged as an alternative to traditional organ transplantation. Decellularization of organs with chemical, physical, and/or biological agents generates natural scaffolds, which can serve as basis for tissue reconstruction. The recellularization of these scaffolds with different cell sources, such as stem cells or adult differentiated cells, can provide an organ with functionality and no immune response after in vivo transplantation on the host. Several studies have focused on improving these techniques, but until now, there is no optimal decellularization method for the kidney available yet. Herein, an overview of the current literature for kidney decellularization and whole-organ recellularization is presented, addressing the pros and cons of the actual techniques already developed, the methods adopted to evaluate the efficacy of the procedures, and the challenges to be overcome in order to achieve an optimal protocol.
Collapse
Affiliation(s)
- Afrânio Côgo Destefani
- Tissue Engineering Core—LUCCAR, Morphology, Federal University of Espírito Santo (UFES), Vitória, Brazil
- Health Sciences Center, Federal University of Espírito Santo (UFES), Vitória, Brazil
- Health Sciences Center, Postgraduate Program in Biotechnology/RENORBIO, Vitória, Brazil
| | - Gabriela Modenesi Sirtoli
- Tissue Engineering Core—LUCCAR, Morphology, Federal University of Espírito Santo (UFES), Vitória, Brazil
- Health Sciences Center, Federal University of Espírito Santo (UFES), Vitória, Brazil
| | - Breno Valentim Nogueira
- Tissue Engineering Core—LUCCAR, Morphology, Federal University of Espírito Santo (UFES), Vitória, Brazil
- Health Sciences Center, Federal University of Espírito Santo (UFES), Vitória, Brazil
- Health Sciences Center, Postgraduate Program in Biotechnology/RENORBIO, Vitória, Brazil
| |
Collapse
|
|
48
|
Wei SY, Wang YX, Zhang QF, Zhao SL, Diao TT, Li JS, Qi WR, He YX, Guo XY, Zhang MZ, Chen JY, Wang XT, Wei QJ, Wang Y, Li B. Multiple Mechanisms are Involved in Salt-Sensitive Hypertension-Induced Renal Injury and Interstitial Fibrosis. Sci Rep 2017; 7:45952. [PMID: 28383024 PMCID: PMC5382679 DOI: 10.1038/srep45952] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 03/08/2017] [Indexed: 12/20/2022] Open
Abstract
Salt-sensitive hypertension (SSHT) leads to kidney interstitial fibrosis. However, the potential mechanisms leading to renal fibrosis have not been well investigated. In present study, Dahl salt-sensitive (DS) rats were divided into three groups: normal salt diet (DSN), high salt diet (DSH) and high salt diet treated with hydrochlorothiazide (HCTZ) (DSH + HCTZ). A significant increase in systolic blood pressure (SBP) was observed 3 weeks after initiating the high salt diet, and marked histological alterations were observed in DSH rats. DSH rats showed obvious podocyte injury, peritubular capillary (PTC) loss, macrophage infiltration, and changes in apoptosis and cell proliferation. Moreover, Wnt/β-catenin signaling was significantly activated in DSH rats. However, HCTZ administration attenuated these changes with decreased SBP. In addition, increased renal and urinary Wnt4 expression was detected with time in DSH rats and was closely correlated with histopathological alterations. Furthermore, these alterations were also confirmed by clinical study. In conclusion, the present study provides novel insight into the mechanisms related to PTC loss, macrophage infiltration and Wnt/β-catenin signaling in SSHT-induced renal injury and fibrosis. Therefore, multi-target therapeutic strategies may be the most effective in preventing these pathological processes. Moreover, urinary Wnt4 may be a noninvasive biomarker for monitoring renal injury after hypertension.
Collapse
Affiliation(s)
- Shi-Yao Wei
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Yu-Xiao Wang
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Qing-Fang Zhang
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Shi-Lei Zhao
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Tian-Tian Diao
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Jian-Si Li
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Wen-Rui Qi
- Financial Mathematics, Beijing Normal University-Hong Kong Baptist University United International College Zhuhai, People’s Republic of China
| | - Yi-Xin He
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Xin-Yu Guo
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Man-Zhu Zhang
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Jian-Yu Chen
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Xiao-Ting Wang
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Qiu-Ju Wei
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Yu Wang
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| | - Bing Li
- Department of Nephrology, Second Affiliated Hospital of Harbin Medical University, Harbin, People’s Republic of China
| |
Collapse
|
|
49
|
Lee C, Jang MJ, Kim BH, Park JY, You D, Jeong IG, Hong JH, Kim CS. Recovery of renal function after administration of adipose-tissue-derived stromal vascular fraction in rat model of acute kidney injury induced by ischemia/reperfusion injury. Cell Tissue Res 2017; 368:603-613. [PMID: 28283911 DOI: 10.1007/s00441-017-2585-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/09/2017] [Indexed: 12/26/2022]
Abstract
Acute kidney injury (AKI) induced by ischemia/reperfusion (I/R) injury is a major challenge in critical care medicine. The purpose of this study is to determine the therapeutic effects of the adipose-tissue-derived stromal vascular fraction (SVF) and the optimal route for SVF delivery in a rat model of AKI induced by I/R injury. Fifty male Sprague-Dawley rats were randomly divided into five groups (10 animals per group): sham, nephrectomy control, I/R injury control, renal arterial SVF infusion and subcapsular SVF injection. To induce AKI by I/R injury, the left renal artery was clamped with a nontraumatic vascular clamp for 40 min, and the right kidney was removed. Rats receiving renal arterial infusion of SVF had a significantly reduced increase in serum creatinine compared with the I/R injury control group at 4 days after I/R injury. The glomerular filtration rate of the renal arterial SVF infusion group was maintained at a level similar to that of the sham and nephrectomy control groups at 14 days after I/R injury. Masson's trichrome staining showed significantly less fibrosis in the renal arterial SVF infusion group compared with that in the I/R injury control group in the outer stripe (P < 0.001). TUNEL labeling showed significantly decreased apoptosis in both the renal arterial SVF infusion and subcapsular SVF injection groups compared with the I/R injury control group in the outer stripe (P < 0.001). Thus, renal function is effectively rescued from AKI induced by I/R injury through the renal arterial administration of SVF in a rat model.
Collapse
Affiliation(s)
- Chunwoo Lee
- Department of Urology, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, South Korea
| | - Myoung Jin Jang
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Bo Hyun Kim
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jin Young Park
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea
| | - Dalsan You
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea
| | - In Gab Jeong
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea
| | - Jun Hyuk Hong
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea
| | - Choung-Soo Kim
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea.
| |
Collapse
|
|
50
|
Collett JA, Mehrotra P, Crone A, Shelley WC, Yoder MC, Basile DP. Endothelial colony-forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury. Am J Physiol Renal Physiol 2017; 312:F897-F907. [PMID: 28228404 DOI: 10.1152/ajprenal.00643.2016] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/16/2017] [Accepted: 02/16/2017] [Indexed: 01/07/2023] Open
Abstract
Damage to endothelial cells contributes to acute kidney injury (AKI) by leading to impaired perfusion. Endothelial colony-forming cells (ECFC) are endothelial precursor cells with high proliferative capacity, pro-angiogenic activity, and in vivo vessel forming potential. We hypothesized that ECFC may ameliorate the degree of AKI and/or promote repair of the renal vasculature following ischemia-reperfusion (I/R). Rat pulmonary microvascular endothelial cells (PMVEC) with high proliferative potential were compared with pulmonary artery endothelial cells (PAEC) with low proliferative potential in rats subjected to renal I/R. PMVEC administration reduced renal injury and hastened recovery as indicated by serum creatinine and tubular injury scores, while PAEC did not. Vehicle-treated control animals showed consistent reductions in renal medullary blood flow (MBF) within 2 h of reperfusion, while PMVEC protected against loss in MBF as measured by laser Doppler. Interestingly, PMVEC mediated protection occurred in the absence of homing to the kidney. Conditioned medium (CM) from human cultured cord blood ECFC also conveyed beneficial effects against I/R injury and loss of MBF. Moreover, ECFC-CM significantly reduced the expression of ICAM-1 and decreased the number of differentiated lymphocytes typically recruited into the kidney following renal ischemia. Taken together, these data suggest that ECFC secrete factors that preserve renal function post ischemia, in part, by preserving microvascular function.
Collapse
Affiliation(s)
- Jason A Collett
- Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, Indiana; and
| | - Purvi Mehrotra
- Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, Indiana; and
| | - Allison Crone
- Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, Indiana; and
| | - W Christopher Shelley
- Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Mervin C Yoder
- Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - David P Basile
- Department of Cellular and Integrative Physiology, Indiana University, Indianapolis, Indiana; and
| |
Collapse
|