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Öz H, Canacankatan N, Antmen ŞE, Aytan H, Tuncel F. 'Investigation of miRNAs That Affect the PI3K/AKT/mTOR Signaling Pathway in Endometrial Cancer'. Cell Biochem Biophys 2025:10.1007/s12013-025-01694-6. [PMID: 39982560 DOI: 10.1007/s12013-025-01694-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
Endometrial cancer is a prevalent type of cancer among women worldwide. The irregularity of the PI3K/AKT/mTOR signaling pathway plays a role in the pathogenesis of many cancer types. MicroRNAs are small noncoding RNAs that play crucial roles in the pathogenesis of different cancer types. MicroRNAs target many key components of the PI3K/AKT/mTOR pathway in human tumors. In this study the PI3K/AKT/mTOR pathway was affected in endometrial cancer, and the expression levels of miR-7, miR-17, miR-145, miR-155, miR-206, miR-221, miR-222 were determined. In addition, in silico analyses were examine the molecular interactions between miRNAs and target genes. Identifying dysregulated miRNA expression in endometrial cancer is important for developing miRNA-based therapeutic strategies. In our study, Grade 1 (n = 16), Grade 2 (n = 16), Grade 3 (n = 16), tissues diagnosed with endometrioid adeno carcinoma, control 1 (n = 16) secretory phase and control 2 (n = 16) proliferative phase healthy endometrial tissues without endometrial cancer were included. miRNA expression analysis was performed using the real-time PCR. In our study, the expression of miR-7-5p, miR-145-5p, and miR-206 decreased, whereas the expression of miR-17-5p, miR-221-3p, and miR-222-3p increased in endometrial cancer (p < 0,05). Statistically significant results were not obtained to for the expression levels of miR-21-5p and miR-155-5p. miR-7-5p targets PIK3CD, PIK3R3, PIK3CB and AKT3, miR-17-5p targets PIK3R1 and AKT3, miR-21-5p target PIK3R1, miR-145-5p target AKT3, miR-155-5p targets PIK3CA and PIK3R1, miR-206 target PIK3C2A, miR-221-3p and miR-222-3p target PIK3R1 as identified via in silico analysis. These results can shed light on the development of molecular-targeted therapy strategies. Treatment strategies can be developed by designing ASOs, LNAs, miRNA antagomirs, or miRNA sponges for upregulated miR-17-5p, miR-221-3p, and miR-222-3p, and miRNA mimics for downregulated miR-7-5p, miR-145-5p, and miR-206.
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Affiliation(s)
- Hasan Öz
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Necmiye Canacankatan
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey.
| | - Şerife Efsun Antmen
- Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, Turkey
| | - Hakan Aytan
- Department of Obstetrics and Gynecology, Faculty of Medicine, Mersin University, Mersin, Turkey
| | - Ferah Tuncel
- Department of Pathology, Faculty of Medicine, Mersin University, Mersin, Turkey
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Nguyen LNT, Pyburn JS, Nguyen NL, Schank MB, Zhao J, Wang L, Leshaodo TO, El Gazzar M, Moorman JP, Yao ZQ. Epigenetic Regulation by lncRNA GAS5/miRNA/mRNA Network in Human Diseases. Int J Mol Sci 2025; 26:1377. [PMID: 39941145 PMCID: PMC11818527 DOI: 10.3390/ijms26031377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/30/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
The interplay between long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) is crucial in the epigenetic regulation of mRNA and protein expression, impacting the development and progression of a plethora of human diseases, such as cancer, cardiovascular disease, inflammatory-associated diseases, and viral infection. Among the many lncRNAs, growth arrest-specific 5 (GAS5) has garnered substantial attention for its evident role in the regulation of significant biological processes such as proliferation, differentiation, senescence, and apoptosis. Through miRNA-mediated signaling pathways, GAS5 modulates disease progression in a cell-type-specific manner, typically by influencing proteins involved in inflammation and cell death. While GAS5 is recognized as a tumor suppressor in cancer, recent reports highlight its broader regulatory capacity in non-cancerous diseases. Its modulation of protein expression through the GAS5/miRNA network has been shown to both mitigate and exacerbate disease, depending on the specific context. Furthermore, the therapeutic potential of GAS5 manipulation, via knockdown or overexpression, offers promising avenues for targeted interventions across human diseases. This review explores the dualistic impacts of the GAS5/miRNA network in conditions such as cancer, cardiovascular disease, viral infections, and inflammatory disorders. Through the evaluation of current evidence, we aim to provide insight into GAS5's biological functions and its implications for future research and therapeutic development.
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Affiliation(s)
- Lam Ngoc Thao Nguyen
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Jaeden S. Pyburn
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Nhat Lam Nguyen
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Madison B. Schank
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Juan Zhao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Ling Wang
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Tabitha O. Leshaodo
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Mohamed El Gazzar
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| | - Jonathan P. Moorman
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA
| | - Zhi Q. Yao
- Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA; (L.N.T.N.); (J.S.P.); (N.L.N.); (M.B.S.); (J.Z.); (L.W.); (T.O.L.); (M.E.G.); (J.P.M.)
- Department of Internal Medicine, Division of Infectious, Inflammatory and Immunologic Diseases, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
- Hepatitis (HCV/HBV/HIV) Program, James H. Quillen VA Medical Center, Department of Veterans Affairs, Johnson City, TN 37614, USA
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Wu J, Zhang C, Li H, Zhang S, Chen J, Qin L. Competing endogenous RNAs network dysregulation in oral cancer: a multifaceted perspective on crosstalk and competition. Cancer Cell Int 2024; 24:431. [PMID: 39725978 DOI: 10.1186/s12935-024-03580-2] [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: 04/26/2024] [Accepted: 11/19/2024] [Indexed: 12/28/2024] Open
Abstract
Oral cancer progresses from asymptomatic to advanced stages, often involving cervical lymph node metastasis, resistance to chemotherapy, and an unfavorable prognosis. Clarifying its potential mechanisms is vital for developing effective theraputic strategies. Recent research suggests a substantial involvement of non-coding RNA (ncRNA) in the initiation and advancement of oral cancer. However, the underlying roles and functions of various ncRNA types in the growth of this malignant tumor remain unclear. Competing endogenous RNAs (ceRNAs) refer to transcripts that can mutually regulate each other at the post-transcriptional level by vying for shared miRNAs. Networks of ceRNAs establish connections between the functions of protein-coding mRNAs and non-coding RNAs, including microRNA, long non-coding RNA, pseudogenic RNA, and circular RNA, piwi-RNA, snoRNA. A growing body of research has indicated that imbalances in ceRNAs networks play a crucial role in various facets of oral cancer, including development, metastasis, migration, invasion, and inflammatory responses. Hence, delving into the regulatory pathways of ceRNAs in oral cancer holds the potential to advance our understanding of the pathological mechanisms, facilitate early diagnosis, and foster targeted drug development for this malignancy. The present review summarized the fundamental role of ceRNA network, discussed the limitations of current ceRNA applications, which have been improved through chemical modification and carrier delivery as new biomarkers for diagnosis and prognosis is expected to offer a groundbreaking therapeutic approach for individuals with oral cancer.
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Affiliation(s)
- Jiajun Wu
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Chanjuan Zhang
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Hongfang Li
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Shuo Zhang
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China
| | - Jingxin Chen
- Department of Oral and Maxillofacial Surgery, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou, 570311, China.
- School of Pharmacy, Hunan University of Chinese Medicine, 300 Xueshi Road, Hanpu Science and Education District, Changsha, Hunan, 410208, China.
| | - Li Qin
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
- Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, China.
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Trabulus S, Zor MS, Alagoz S, Dincer MT, Meşe M, Yilmaz E, Tahir Turanli E, Seyahi N. Profiling of five urinary exosomal miRNAs for the differential diagnosis of patients with diabetic kidney disease and focal segmental glomerulosclerosis. PLoS One 2024; 19:e0312470. [PMID: 39471136 PMCID: PMC11521285 DOI: 10.1371/journal.pone.0312470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 10/08/2024] [Indexed: 11/01/2024] Open
Abstract
OBJECTIVE The objective of this study is to investigate the diagnostic utility of microRNAs (miRNAs) for distinguishing between urine samples from patients with Diabetic Kidney Disease (DKD) and those with Focal Segmental Glomerulosclerosis (FSGS). METHODS In this multicentric, cross-sectional investigation, we enrolled patients diagnosed with DKD, individuals with primary biopsy-proven FSGS, and healthy controls. The top 5 miRNAs (hsa-mir-21, hsa-mir-30a, hsa-mir-193a, hsa-mir-196a, hsa-mir-200a) were selected to quantify miRNAs in urine samples. Isolation of targeted miRNAs was performed from urinary exosomes, and the quantitative profile of the isolated miRNAs was measured by RT-qPCR. The ΔΔCt method was implemented to calculate the fold differences between disease and control samples. RESULTS Thirteen DKD patients, 11 FSGS patients, and 14 healthy controls were included in this study. Hsa-mir-21 and hsa-mir-30a exhibited distinct regulation in both groups, with upregulation observed in FSGS and downregulation in DKD (hsa-mir-21 in DKD (0.668 ± 0.25, p < 0.0005) and FSGS (2.267 ± 1.138, p < 0.0077); hsa-mir-30a in DKD (0.874 ± 0.254, p = 0.079) and FSGS (1.378 ± 0.312, p < 0.0006)). Hsa-mir-193a exhibited significant dysregulation in DKD (1.017 ± 0.413, p < 0.029) but not in FSGS (4.18 ± 1.528, p = 0.058). Hsa-mir-196a and hsa-mir-200a showed upregulation in patient groups (hsa-mir-196a in DKD (1.278 ± 0.527, p = 0.074) and FSGS (2.47 ± 0.911, p < 0.0003); hsa-mir-200a in DKD (1.909 ± 0.825, p = 0.082) and FSGS (1.301 ± 0.358, p < 0.008)). CONCLUSION Specific miRNAs, particularly miR-21, miR-30a, miR-196a, and miR-200a, might play a role in the pathogenesis of kidney diseases and could potentially serve as biomarkers to distinguish between FSGS and DKD patients.
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Affiliation(s)
- Sinan Trabulus
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Mehmet Seyit Zor
- Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Technical University, Istanbul, Turkey
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Selma Alagoz
- Division of Nephrology, Bagcilar Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Mevlut Tamer Dincer
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Meral Meşe
- Division of Nephrology, Kartal Lutfi Kirdar Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Erkan Yilmaz
- Tissue Typing Laboratory, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Eda Tahir Turanli
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Acibadem University, Istanbul, Turkey
- Program of Molecular Biology and Genetics, Institute of Natural Sciences, Acibadem University, Istanbul, Turkey
| | - Nurhan Seyahi
- Division of Nephrology, Department of Internal Medicine, Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Istanbul, Turkey
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Tan P, Hua Y, Yuan B, Liu X, Chen X, Zeng WN, Zeng Q, Zhu X, Zhang X. PI3K/AKT/mTOR signaling regulates BCP ceramic-induced osteogenesis. J Mater Chem B 2024; 12:7591-7603. [PMID: 38984467 DOI: 10.1039/d4tb01335b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/11/2024]
Abstract
An increasing number of studies demonstrate that biphasic calcium phosphate (BCP) ceramics can induce bone regeneration. However, the underlying molecular mechanisms involved are still poorly understood. This work was proposed to investigate how PI3K/AKT/mTOR signaling influenced the osteogenesis mediated by BCP ceramics. The results showed that incubation with BCP ceramics promoted the proliferation of murine bone marrow-derived mesenchymal stem cells (BMSCs) in a time-dependent manner. The resulting cell proliferation was then suppressed by the selective inhibition of either PI3K, AKT, or mTOR signaling activation. Next, we confirmed that BCP ceramics up-regulated the phosphorylation levels of AKT and mTOR in BMSCs, suggesting the ability of BCP ceramics to drive the activation of PI3K/AKT/mTOR signaling in BMSCs. Furthermore, the blockade of PI3K/AKT/mTOR signaling prevented BCP ceramics-induced osteogenic differentiation and pro-angiogenesis of BMSCs by down-regulating the expression of genes encoding OPN, RUNX2 or VEGF. Moreover, the PI3K/AKT/mTOR signaling blockade suppressed stem cell infiltration and new bone formation in the implants following intra-muscular implantation of BCP ceramics in mice. Therefore, our results suggested that PI3K/AKT/mTOR signaling played a critical regulatory role in BCP ceramic-induced osteogenesis.
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Affiliation(s)
- Peijie Tan
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Yuchen Hua
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Bo Yuan
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Xiaoyang Liu
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuening Chen
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Wei-Nan Zeng
- Orthopedic Research Institution, Department of Orthopedics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qin Zeng
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, China
| | - Xiangdong Zhu
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
| | - Xingdong Zhang
- National Engineering Research Center for Biomaterials, Sichuan University, No. 29 Wangjiang Road, Chengdu 610064, China.
- NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu 610064, China
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Rajabi S, Saberi S, Najafipour H, Askaripour M, Rajizadeh MA, Shahraki S, Kazeminia S. Interaction of estradiol and renin-angiotensin system with microRNAs-21 and -29 in renal fibrosis: focus on TGF-β/smad signaling pathway. Mol Biol Rep 2024; 51:137. [PMID: 38236310 DOI: 10.1007/s11033-023-09127-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 12/06/2023] [Indexed: 01/19/2024]
Abstract
Kidney fibrosis is one of the complications of chronic kidney disease (CKD (and contributes to end-stage renal disease which requires dialysis and kidney transplantation. Several signaling pathways such as renin-angiotensin system (RAS), microRNAs (miRNAs) and transforming growth factor-β1 (TGF-β1)/Smad have a prominent role in pathophysiology and progression of renal fibrosis. Activation of classical RAS, the elevation of angiotensin II (Ang II) production and overexpression of AT1R, develop renal fibrosis via TGF-β/Smad pathway. While the non-classical RAS arm, Ang 1-7/AT2R, MasR reveals an anti-fibrotic effect via antagonizing Ang II. This review focused on studies illustrating the interaction of RAS with sexual female hormone estradiol and miRNAs in the progression of renal fibrosis with more emphasis on the TGF-β signaling pathway. MiRNAs, especially miRNA-21 and miRNA-29 showed regulatory effects in renal fibrosis. Also, 17β-estradiol (E2) is a renoprotective hormone that improved renal fibrosis. Beneficial effects of ACE inhibitors and ARBs are reported in the prevention of renal fibrosis in patients. Future studies are also merited to delineate the new therapy strategies such as miRNAs targeting, combination therapy of E2 or HRT, ACEis, and ARBs with miRNAs mimics and antagomirs in CKD to provide a new therapeutic approach for kidney patients.
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Affiliation(s)
- Soodeh Rajabi
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Shadan Saberi
- Department of Physiology and Pharmacology, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran
| | - Hamid Najafipour
- Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
| | - Majid Askaripour
- Department of Physiology, School of Medicine, Bam University of Medical Sciences, Bam, Iran.
| | - Mohammad Amin Rajizadeh
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Sarieh Shahraki
- Department of Physiology and Pharmacology, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Sara Kazeminia
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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Mitra P, Jana S, Roy S. Insights into the Therapeutic uses of Plant Derive Phytocompounds onDiabetic Nephropathy. Curr Diabetes Rev 2024; 20:e230124225973. [PMID: 38265383 DOI: 10.2174/0115733998273395231117114600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 01/25/2024]
Abstract
Diabetic nephropathy (DN) is one of the primary consequences of diabetes mellitus, affecting many people worldwide and is the main cause of death under the age of sixty. Reactive oxygen species (ROS) production rises during hyperglycemia and is crucial to the development of diabetic complications. Advanced glycation end products (AGEs) are produced excessively in a diabetic state and are accumulated in the kidney, where they change renal architecture and impair renal function. Another important targeted pathway for the formation of DN includes nuclear factor kappa-B (NF-kB), Nuclear factor E2-related factor 2 (Nrf2), NLR family pyrin domain containing 3 (NLRP3), protein kinase B/mammalian target of rapamycin (Akt/mTOR), and autophagy. About 40% of individuals with diabetes eventually acquire diabetic kidney disease and end-stage renal disease that needs hemodialysis, peritoneal dialysis, or kidney transplantation to survive. The current state of acceptable therapy for this kidney ailment is limited. The studies revealed that some naturally occurring bioactive substances might shield the kidney by controlling oxidative stress, renal fibrosis, inflammation, and autophagy. In order to provide new potential therapeutic lead bioactive compounds for contemporary drug discovery and clinical management of DN, this review was designed to examine the various mechanistic pathways by which conventional plants derive phytocompounds that are effective for the control and treatment of DN.
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Affiliation(s)
- Palash Mitra
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Kuturiya, Bhadutala, Midnapore 721129, India
- Biodiversity and Environmental Studies Research Center, Midnapore City College, Kuturiya, Bhadutala, Midnapore 721129, Paschim Medinipur, West Bengal, India
| | - Sahadeb Jana
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Kuturiya, Bhadutala, Midnapore 721129, India
- Biodiversity and Environmental Studies Research Center, Midnapore City College, Kuturiya, Bhadutala, Midnapore 721129, Paschim Medinipur, West Bengal, India
| | - Suchismita Roy
- Nutrition Research Laboratory, Department of Paramedical and Allied Health Sciences, Midnapore City College, Kuturiya, Bhadutala, Midnapore 721129, India
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Khalaji A, Mehrtabar S, Jabraeilipour A, Doustar N, Rahmani Youshanlouei H, Tahavvori A, Fattahi P, Alavi SMA, Taha SR, Fazlollahpour-Naghibi A, Shariat Zadeh M. Inhibitory effect of microRNA-21 on pathways and mechanisms involved in cardiac fibrosis development. Ther Adv Cardiovasc Dis 2024; 18:17539447241253134. [PMID: 38819836 PMCID: PMC11143841 DOI: 10.1177/17539447241253134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 04/18/2024] [Indexed: 06/01/2024] Open
Abstract
Cardiac fibrosis is a pivotal cardiovascular disease (CVD) process and represents a notable health concern worldwide. While the complex mechanisms underlying CVD have been widely investigated, recent research has highlighted microRNA-21's (miR-21) role in cardiac fibrosis pathogenesis. In this narrative review, we explore the molecular interactions, focusing on the role of miR-21 in contributing to cardiac fibrosis. Various signaling pathways, such as the RAAS, TGF-β, IL-6, IL-1, ERK, PI3K-Akt, and PTEN pathways, besides dysregulation in fibroblast activity, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs cause cardiac fibrosis. Besides, miR-21 in growth factor secretion, apoptosis, and endothelial-to-mesenchymal transition play crucial roles. miR-21 capacity regulatory function presents promising insights for cardiac fibrosis. Moreover, this review discusses numerous approaches to control miR-21 expression, including antisense oligonucleotides, anti-miR-21 compounds, and Notch signaling modulation, all novel methods of cardiac fibrosis inhibition. In summary, this narrative review aims to assess the molecular mechanisms of cardiac fibrosis and its essential miR-21 function.
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Affiliation(s)
- Amirreza Khalaji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166/15731, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saba Mehrtabar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Connective Tissue Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Nadia Doustar
- Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | | | - Amir Tahavvori
- Department of Internal Medicine, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Payam Fattahi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Seyed Reza Taha
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Andarz Fazlollahpour-Naghibi
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Trivedi A, Bose D, Saha P, Roy S, More M, Skupsky J, Klimas NG, Chatterjee S. Prolonged Antibiotic Use in a Preclinical Model of Gulf War Chronic Multisymptom-Illness Causes Renal Fibrosis-like Pathology via Increased micro-RNA 21-Induced PTEN Inhibition That Is Correlated with Low Host Lachnospiraceae Abundance. Cells 2023; 13:56. [PMID: 38201260 PMCID: PMC10777912 DOI: 10.3390/cells13010056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/21/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.
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Affiliation(s)
- Ayushi Trivedi
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Dipro Bose
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Punnag Saha
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Subhajit Roy
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | - Madhura More
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
| | | | - Nancy G. Klimas
- Institute for Neuro-Immune Medicine, College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL 33328, USA;
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, Department of Environmental and Occupational Health, Program in Public Health, Susan and Henry Samueli College of Health Sciences, University of California, Irvine, CA 92697, USA; (A.T.); (D.B.); (P.S.); (S.R.); (M.M.)
- Long Beach VA Medical Center, Long Beach, CA 90822, USA;
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of California, Irvine, CA 92697, USA
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10
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Prosseda PP, Dannewitz Prosseda S, Tran M, Liton PB, Sun Y. Crosstalk between the mTOR pathway and primary cilia in human diseases. Curr Top Dev Biol 2023; 155:1-37. [PMID: 38043949 PMCID: PMC11227733 DOI: 10.1016/bs.ctdb.2023.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2023]
Abstract
Autophagy is a fundamental catabolic process whereby excessive or damaged cytoplasmic components are degraded through lysosomes to maintain cellular homeostasis. Studies of mTOR signaling have revealed that mTOR controls biomass generation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Primary cilia, the assembly of which depends on kinesin molecular motors, serve as sensory organelles and signaling platforms. Given these pathways' central role in maintaining cellular and physiological homeostasis, a connection between mTOR and primary cilia signaling is starting to emerge in a variety of diseases. In this review, we highlight recent advances in our understanding of the complex crosstalk between the mTOR pathway and cilia and discuss its function in the context of related diseases.
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Affiliation(s)
- Philipp P Prosseda
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, United States
| | | | - Matthew Tran
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Paloma B Liton
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC, United States
| | - Yang Sun
- Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA, United States; Palo Alto Veterans Administration Medical Center, Palo Alto, CA, United States.
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11
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Sun L, Ding M, Chen F, Zhu D, Xie X. Long non‑coding RNA L13Rik promotes high glucose-induced mesangial cell hypertrophy and matrix protein expression by regulating miR-2861/CDKN1B axis. PeerJ 2023; 11:e16170. [PMID: 37868060 PMCID: PMC10586299 DOI: 10.7717/peerj.16170] [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: 05/01/2023] [Accepted: 09/03/2023] [Indexed: 10/24/2023] Open
Abstract
Background Diabetic nephropathy (DN) is a frequent microvascular complication of diabetes. Glomerular mesangial cell (MC) hypertrophy occurs at the initial phase of DN and plays a critical role in the pathogenesis of DN. Given the role of long non coding RNA (lncRNA) in regulating MC hypertrophy and extracellular matrix (ECM) accumulation, our aim was to identify functional lncRNAs during MC hypertrophy. Methods Here, an lncRNA, C920021L13Rik (L13Rik for short), was identified to be up-regulated in DN progression. The expression of L13Rik in DN patients and diabetic mice was assessed using quantitative real-time PCR (qRT-PCR), and the function of L13Rik in regulating HG-induced MC hypertrophy and ECM accumulation was assessed through flow cytometry and western blotting analysis. Results The L13Rik levels were significantly increased while the miR-2861 levels were decreased in the peripheral blood of DN patients, the renal tissues of diabetic mice, and HG-treated MCs. Functionally, both L13Rik depletion and miR-2861 overexpression effectively reduced HG-induced cell hypertrophy and ECM accumulation. Mechanistically, L13Rik functioned as a competing endogenous RNA (ceRNA) to sponge miR-2861, resulting in the de-repression of cyclin-dependent kinase inhibitor 1B (CDKN1B), a gene known to regulate cell cycle and MC hypertrophy. Conclusions Collectively, the current results demonstrate that up-regulated L13Rik is correlated with DN and may be a hopeful therapeutic target for DN.
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Affiliation(s)
- Linlin Sun
- Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Miao Ding
- Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fuhua Chen
- Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dingyu Zhu
- Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xinmiao Xie
- Nephrology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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12
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Das F, Ghosh-Choudhury N, Maity S, Kasinath BS, Ghosh Choudhury G. TGFβ instructs mTORC2 to activate PKCβII for increased TWIST1 expression in proximal tubular epithelial cell injury. FEBS Lett 2023; 597:1300-1316. [PMID: 36775967 DOI: 10.1002/1873-3468.14599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/13/2023] [Accepted: 02/02/2023] [Indexed: 02/14/2023]
Abstract
The plasticity of proximal tubular epithelial cells in response to TGFβ contributes to the expression of TWIST1 to drive renal fibrosis. The mechanism of TWIST1 expression is not known. We show that both PI3 kinase and its target mTORC2 increase TGFβ-induced TWIST1 expression. TGFβ enhances phosphorylation on Ser-660 in the protein kinase C βII (PKCβII) hydrophobic motif site. Remarkably, phosphorylation-deficient PKCβIIS660A, kinase-dead PKCβII, and PKCβII knockdown blocked TWIST1 expression by TGFβ. Inhibition of TWIST1 arrested TGFβ-induced tubular cell hypertrophy and the expression of fibronectin, collagen I (α2), and α-smooth muscle actin. By contrast, TWIST1 overexpression induced these pathologies. Interestingly, the inhibition of PKCβII reduced these phenomena, which were countered by the expression of TWIST1. These results provide the first evidence for the involvement of the mTORC2-PKCβII axis in TWIST1 expression to promote tubular cell pathology.
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Affiliation(s)
- Falguni Das
- 1VA Research and 4Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, TX, 78229, USA.,Department of Medicine, UT Health San Antonio, TX, USA
| | | | - Soumya Maity
- Department of Medicine, UT Health San Antonio, TX, USA
| | | | - Goutam Ghosh Choudhury
- 1VA Research and 4Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, TX, 78229, USA.,Department of Medicine, UT Health San Antonio, TX, USA.,Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA
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13
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Chen JY, Yiu WH, Tang PMK, Tang SCW. New insights into fibrotic signaling in renal cell carcinoma. Front Cell Dev Biol 2023; 11:1056964. [PMID: 36910160 PMCID: PMC9996540 DOI: 10.3389/fcell.2023.1056964] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/17/2023] [Indexed: 02/23/2023] Open
Abstract
Fibrotic signaling plays a pivotal role in the development and progression of solid cancers including renal cell carcinoma (RCC). Intratumoral fibrosis (ITF) and pseudo-capsule (PC) fibrosis are significantly correlated to the disease progression of renal cell carcinoma. Targeting classic fibrotic signaling processes such as TGF-β signaling and epithelial-to-mesenchymal transition (EMT) shows promising antitumor effects both preclinically and clinically. Therefore, a better understanding of the pathogenic mechanisms of fibrotic signaling in renal cell carcinoma at molecular resolution can facilitate the development of precision therapies against solid cancers. In this review, we systematically summarized the latest updates on fibrotic signaling, from clinical correlation and molecular mechanisms to its therapeutic strategies for renal cell carcinoma. Importantly, we examined the reported fibrotic signaling on the human renal cell carcinoma dataset at the transcriptome level with single-cell resolution to assess its translational potential in the clinic.
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Affiliation(s)
- Jiao-Yi Chen
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Wai-Han Yiu
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Sydney Chi-Wai Tang
- Division of Nephrology, Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
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14
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MicroRNA-10 Family Promotes the Epithelial-to-Mesenchymal Transition in Renal Fibrosis by the PTEN/Akt Pathway. Curr Issues Mol Biol 2022; 44:6059-6074. [PMID: 36547074 PMCID: PMC9776942 DOI: 10.3390/cimb44120413] [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: 11/03/2022] [Revised: 11/24/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
Renal fibrosis (RF) is a common reason for renal failure, and epithelial-mesenchymal transition (EMT) is a vital mechanism that promotes the development of RF. It is known that microRNA-10 (miR-10) plays an important role in cancer EMT; however, whether it takes part in the EMT process of RF remains unclear. Therefore, we established an in vivo model of unilateral ureteral obstruction (UUO), and an in vitro model using TGF-β1, to investigate whether and how miR-10a and miR-10b take part in the EMT of RF. In addition, the combinatorial effects of miR-10a and miR-10b were assessed. We discovered that miR-10a and miR-10b are overexpressed in UUO mice, and miR-10a, miR-10b, and miRs-10a/10b knockout attenuated RF and EMT in UUO-treated mouse kidneys. Moreover, miR-10a and miR-10b overexpression combinatorially promoted RF and EMT in TGF-β1-treated HK-2 cells. Inhibiting miR-10a and miR-10b attenuated RF and EMT induced by TGF-β1. Mechanistically, miR-10a and miR-10b suppressed PTEN expression by binding to its mRNA3'-UTR and promoting the Akt pathway. Moreover, PTEN overexpression reduced miR-10a and miR-10b effects on Akt phosphorylation (p-Akt), RF, and EMT in HK-2 cells treated with TGF-β1. Taken together, miR-10a and miR-10b act combinatorially to negatively regulate PTEN, thereby activating the Akt pathway and promoting the EMT process, which exacerbates RF progression.
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15
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Zeng Z, Cai J, Liao Y, Sun S, Xie L. Progress in the effect of microRNA-21 on diseases via autophagy. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:936-941. [PMID: 36039591 PMCID: PMC10930284 DOI: 10.11817/j.issn.1672-7347.2022.210647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Indexed: 06/15/2023]
Abstract
Autophagy is a regulatory mechanism that packages damaged organelles, proteins, and pathogens to form vesicles and transports to lysosomes for degradation, enabling the recycle of useful components. Therefore, autophagy plays an important role in biological growth regulation and homeostasis. In the past two decades, growing evidence has shown that microRNA (miRNA) is closely related to autophagy. MiRNA-21 promotes or inhibits autophagy via regulating relevant pathways for different downstream target genes, and plays a role in tumors, ischemia-reperfusion injury, and other diseases.
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Affiliation(s)
- Zhengpeng Zeng
- Center of Health Management, Third Xiangya Hospital, Central South University, Changsha 410013.
- Department of Respiratory and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Jinwen Cai
- Department of Respiratory and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Yumei Liao
- Department of Respiratory and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China
| | - Shenghua Sun
- Department of Respiratory and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China.
| | - Lihua Xie
- Department of Respiratory and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China.
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16
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Adeva-Andany MM, Carneiro-Freire N. Biochemical composition of the glomerular extracellular matrix in patients with diabetic kidney disease. World J Diabetes 2022; 13:498-520. [PMID: 36051430 PMCID: PMC9329837 DOI: 10.4239/wjd.v13.i7.498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/19/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
In the glomeruli, mesangial cells produce mesangial matrix while podocytes wrap glomerular capillaries with cellular extensions named foot processes and tether the glomerular basement membrane (GBM). The turnover of the mature GBM and the ability of adult podocytes to repair injured GBM are unclear. The actin cytoskeleton is a major cytoplasmic component of podocyte foot processes and links the cell to the GBM. Predominant components of the normal glomerular extracellular matrix (ECM) include glycosaminoglycans, proteoglycans, laminins, fibronectin-1, and several types of collagen. In patients with diabetes, multiorgan composition of extracellular tissues is anomalous, including the kidney, so that the constitution and arrangement of glomerular ECM is profoundly altered. In patients with diabetic kidney disease (DKD), the global quantity of glomerular ECM is increased. The level of sulfated proteoglycans is reduced while hyaluronic acid is augmented, compared to control subjects. The concentration of mesangial fibronectin-1 varies depending on the stage of DKD. Mesangial type III collagen is abundant in patients with DKD, unlike normal kidneys. The amount of type V and type VI collagens is higher in DKD and increases with the progression of the disease. The GBM contains lower amount of type IV collagen in DKD compared to normal tissue. Further, genetic variants in the α3 chain of type IV collagen may modulate susceptibility to DKD and end-stage kidney disease. Human cellular models of glomerular cells, analyses of human glomerular proteome, and improved microscopy procedures have been developed to investigate the molecular composition and organization of the human glomerular ECM.
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17
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Das F, Ghosh-Choudhury N, Maity S, Kasinath BS, Choudhury GG. Oncoprotein DJ-1 interacts with mTOR complexes to effect transcription factor Hif1α-dependent expression of collagen I (α2) during renal fibrosis. J Biol Chem 2022; 298:102246. [PMID: 35835217 PMCID: PMC9399488 DOI: 10.1016/j.jbc.2022.102246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 06/21/2022] [Accepted: 06/22/2022] [Indexed: 11/27/2022] Open
Abstract
Proximal tubular epithelial cells respond to transforming growth factor β (TGFβ) to synthesize collagen I (α2) during renal fibrosis. The oncoprotein DJ-1 has previously been shown to promote tumorigenesis and prevent apoptosis of dopaminergic neurons; however, its role in fibrosis signaling is unclear. Here, we show TGFβ-stimulation increased expression of DJ-1, which promoted noncanonical mTORC1 and mTORC2 activities. We show DJ-1 augmented the phosphorylation/activation of PKCβII, a direct substrate of mTORC2. In addition, coimmunoprecipitation experiments revealed association of DJ-1 with Raptor and Rictor, exclusive subunits of mTORC1 and mTORC2, respectively, as well as with mTOR kinase. Interestingly, siRNAs against DJ-1 blocked TGFβ-stimulated expression of collagen I (α2), while expression of DJ-1 increased expression of this protein. In addition, expression of dominant negative PKCβII and siRNAs against PKCβII significantly inhibited TGFβ-induced collagen I (α2) expression. In fact, constitutively active PKCβII abrogated the effect of siRNAs against DJ-1, suggesting a role of PKCβII downstream of this oncoprotein. Moreover, we demonstrate expression of collagen I (α2) stimulated by DJ-1 and its target PKCβII is dependent on the transcription factor hypoxia-inducible factor 1α (Hif1α). Finally, we show in the renal cortex of diabetic rats that increased TGFβ was associated with enhanced expression of DJ-1 and activation of mTOR and PKCβII, concomitant with increased Hif1α and collagen I (α2). Overall, we identified that DJ-1 affects TGFβ-induced expression of collagen I (α2) via an mTOR-, PKCβII-, and Hif1α-dependent mechanism to regulate renal fibrosis.
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Affiliation(s)
- Falguni Das
- VA Research, South Texas Veterans Health Care System, San Antonio, Texas; Department of Medicine, UT Health San Antonio, Texas
| | | | - Soumya Maity
- Department of Medicine, UT Health San Antonio, Texas
| | | | - Goutam Ghosh Choudhury
- VA Research, South Texas Veterans Health Care System, San Antonio, Texas; Department of Medicine, UT Health San Antonio, Texas; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas.
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18
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Anti-Cancer Effects of Dietary Polyphenols via ROS-Mediated Pathway with Their Modulation of MicroRNAs. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27123816. [PMID: 35744941 PMCID: PMC9227902 DOI: 10.3390/molecules27123816] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 12/23/2022]
Abstract
Consumption of coffee, tea, wine, curry, and soybeans has been linked to a lower risk of cancer in epidemiological studies. Several cell-based and animal studies have shown that dietary polyphenols like chlorogenic acid, curcumin, epigallocatechin-3-O-gallate, genistein, quercetin and resveratrol play a major role in these anticancer effects. Several mechanisms have been proposed to explain the anticancer effects of polyphenols. Depending on the cellular microenvironment, these polyphenols can exert double-faced actions as either an antioxidant or a prooxidant, and one of the representative anticancer mechanisms is a reactive oxygen species (ROS)-mediated mechanism. These polyphenols can also influence microRNA (miR) expression. In general, they can modulate the expression/activity of the constituent molecules in ROS-mediated anticancer pathways by increasing the expression of tumor-suppressive miRs and decreasing the expression of oncogenic miRs. Thus, miR modulation may enhance the anticancer effects of polyphenols through the ROS-mediated pathways in an additive or synergistic manner. More precise human clinical studies on the effects of dietary polyphenols on miR expression will provide convincing evidence of the preventive roles of dietary polyphenols in cancer and other diseases.
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Negative regulators of TGF-β1 signaling in renal fibrosis; pathological mechanisms and novel therapeutic opportunities. Clin Sci (Lond) 2021; 135:275-303. [PMID: 33480423 DOI: 10.1042/cs20201213] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/23/2020] [Accepted: 01/08/2021] [Indexed: 02/06/2023]
Abstract
Elevated expression of the multifunctional cytokine transforming growth factor β1 (TGF-β1) is causatively linked to kidney fibrosis progression initiated by diabetic, hypertensive, obstructive, ischemic and toxin-induced injury. Therapeutically relevant approaches to directly target the TGF-β1 pathway (e.g., neutralizing antibodies against TGF-β1), however, remain elusive in humans. TGF-β1 signaling is subjected to extensive negative control at the level of TGF-β1 receptor, SMAD2/3 activation, complex assembly and promoter engagement due to its critical role in tissue homeostasis and numerous pathologies. Progressive kidney injury is accompanied by the deregulation (loss or gain of expression) of several negative regulators of the TGF-β1 signaling cascade by mechanisms involving protein and mRNA stability or epigenetic silencing, further amplifying TGF-β1/SMAD3 signaling and fibrosis. Expression of bone morphogenetic proteins 6 and 7 (BMP6/7), SMAD7, Sloan-Kettering Institute proto-oncogene (Ski) and Ski-related novel gene (SnoN), phosphate tensin homolog on chromosome 10 (PTEN), protein phosphatase magnesium/manganese dependent 1A (PPM1A) and Klotho are dramatically decreased in various nephropathies in animals and humans albeit with different kinetics while the expression of Smurf1/2 E3 ligases are increased. Such deregulations frequently initiate maladaptive renal repair including renal epithelial cell dedifferentiation and growth arrest, fibrotic factor (connective tissue growth factor (CTGF/CCN2), plasminogen activator inhibitor type-1 (PAI-1), TGF-β1) synthesis/secretion, fibroproliferative responses and inflammation. This review addresses how loss of these negative regulators of TGF-β1 pathway exacerbates renal lesion formation and discusses the therapeutic value in restoring the expression of these molecules in ameliorating fibrosis, thus, presenting novel approaches to suppress TGF-β1 hyperactivation during chronic kidney disease (CKD) progression.
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20
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Wehbe Z, Kreydiyyeh S. Cow's milk may be delivering potentially harmful undetected cargoes to humans. Is it time to reconsider dairy recommendations? Nutr Rev 2021; 80:874-888. [PMID: 34338770 DOI: 10.1093/nutrit/nuab046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Mammalian evolution has shaped milk into a species-specific vehicle for post-natal development, continuing what began within the mother's womb. Increased consumption of the mother's breast milk is associated with the most adequate metabolic programming and lowers the incidence of the diseases of civilization during adulthood. An abundance of short sequences of RNA, known as microRNA, exists in mammalian breast milk, enclosed within robust small extracellular vesicles known as exosomes. These microRNAs can epigenetically regulate over 60% of human genes. When cow's milk is consumed by humans, the bovine exosomes are transported through the gastrointestinal tract, detected intact in the blood stream, and taken up by target cells, where they alter protein expression. The aim of this review was to highlight the role of dairy exosomes and microRNA, and of the type of dairy product consumed, in human diseases. Given that microRNAs are involved in a vast array of physiological processes and associated with several diseases, perhaps caution should be practiced with regard to human consumption of dairy, particularly for individuals within developmentally critical time frames, such as pregnant and lactating mothers, and young children.
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Affiliation(s)
- Zena Wehbe
- Z. Wehbe and S. Kreydiyyeh are with the Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
| | - Sawsan Kreydiyyeh
- Z. Wehbe and S. Kreydiyyeh are with the Department of Biology, Faculty of Arts and Sciences, American University of Beirut, Beirut, Lebanon
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21
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Aashaq S, Batool A, Mir SA, Beigh MA, Andrabi KI, Shah ZA. TGF-β signaling: A recap of SMAD-independent and SMAD-dependent pathways. J Cell Physiol 2021; 237:59-85. [PMID: 34286853 DOI: 10.1002/jcp.30529] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 06/06/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022]
Abstract
Transforming growth factor-β (TGF-β) is a proinflammatory cytokine known to control a diverse array of pathological and physiological conditions during normal development and tumorigenesis. TGF-β-mediated physiological effects are heterogeneous and vary among different types of cells and environmental conditions. TGF-β serves as an antiproliferative agent and inhibits tumor development during primary stages of tumor progression; however, during the later stages, it encourages tumor development and mediates metastatic progression and chemoresistance. The fundamental elements of TGF-β signaling have been divulged more than a decade ago; however, the process by which the signals are relayed from cell surface to nucleus is very complex with additional layers added in tumor cell niches. Although the intricate understanding of TGF-β-mediated signaling pathways and their regulation are still evolving, we tried to make an attempt to summarize the TGF-β-mediated SMAD-dependent andSMAD-independent pathways. This manuscript emphasizes the functions of TGF-β as a metastatic promoter and tumor suppressor during the later and initial phases of tumor progression respectively.
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Affiliation(s)
- Sabreena Aashaq
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
| | - Asiya Batool
- Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Srinagar, JK, India
| | | | | | | | - Zaffar Amin Shah
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, JK, India
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22
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Abstract
Rationale & Objective Previous studies have suggested that microRNA-21 (miR-21) plays an important role in kidney fibrosis. We examined the relationship between intrarenal miR-21 level and rate of kidney function loss in immunoglobulin A nephropathy (IgAN). Study Design Prospective cohort study. Setting & Participants 40 patients with IgAN and 10 with hypertensive nephrosclerosis as controls. Predictors miR-21 levels in kidney biopsy specimen and urinary sediment, quantified as ratio to the housekeeping gene. Outcomes Kidney event–free survival and rate of kidney function decline. Analytic Approach Time-to-event and correlation analysis. Results The IgAN group had significantly higher intrarenal miR-21 expression compared with the hypertensive nephrosclerosis group (1.71 [IQR, 0.99-2.77] vs 0.31 [IQR, 0.25-1.32]; P < 0.0001), but urinary miR-21 levels were similar. Intrarenal miR-21 expression had significant but modest correlation with severity of glomerulosclerosis (r = 0.293; P = 0.05) and tubulointerstitial fibrosis (r = 0.341; P = 0.03). Patients with high intrarenal miR-21 expression had significantly higher risk for developing kidney end points compared with those with low expression (log-rank test, P = 0.017). Univariate Cox analysis showed that intrarenal miR-21 expression significantly predicted the development of kidney end points (unadjusted HR, 1.586; 95% CI, 1.179-2.134; P = 0.002). However, the result was just short of statistical significance after adjusting for the severity of histologic damage (P = 0.06). There was also a significant correlation between intrarenal miR-21 expression and the slope of kidney function decline by univariate analysis (r = −0.399; P = 0.02). Limitations Small sample size; uncertain cellular origin of miR-21. Conclusions We found that intrarenal miR-21 expression is increased in patients with IgAN, modestly correlated with the severity of histologic damage, and predictive of subsequent kidney function loss.
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El-Said YAM, Sallam NAA, Ain-Shoka AAM, Abdel-Latif HAT. Geraniol ameliorates diabetic nephropathy via interference with miRNA-21/PTEN/Akt/mTORC1 pathway in rats. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2020; 393:2325-2337. [PMID: 32666288 DOI: 10.1007/s00210-020-01944-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 07/07/2020] [Indexed: 12/15/2022]
Abstract
Deregulated activity of protein kinase B/mammalian target of rapamycin complex-1 (Akt/mTORC1) incites crucial pathological characteristics of diabetic nephropathy. The acyclic monoterpene geraniol has been recently reported to possess antidiabetic effects; however, its potential renoprotective effect in diabetes has not yet been elucidated. This study aimed to assess the possible modulatory effect of geraniol on the Akt/mTORC1 pathway in diabetes-induced nephropathy in rats compared to the standard antidiabetic drug gliclazide. Geraniol and gliclazide was administered daily to diabetic rats for 6 weeks starting on the 3rd-day post diabetes induction by streptozotocin (STZ). Geraniol amended the deteriorated renal function (serum creatinine; blood urea nitrogen). It exerted a remarkable antihyperglycemic effect that is comparable to that of gliclazide and suppressed the fibrotic marker, transforming growth factor-β. Geraniol restored redox balance and inhibited lipid peroxidation by reducing nicotine amide adenine dinucleotide phosphate oxidase and enhancing the antioxidant enzyme, superoxide dismutase. These beneficial effects were associated with a robust downregulation of miRNA-21 and consequently, reversion of tumor suppressor protein phosphatase and tension homolog (PTEN)/Akt/mTORC1 cue and its downstream proteins required for mesangial cell proliferation and matrix protein synthesis. The current study indicates that geraniol interfered with miRNA-21/ PTEN/AKT/mTORC1 pathway signaling that contributes largely to the progression of mesangial expansion and extracellular matrix deposition in diabetic nephropathy.
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Gui Y, Dai C. mTOR Signaling in Kidney Diseases. KIDNEY360 2020; 1:1319-1327. [PMID: 35372878 PMCID: PMC8815517 DOI: 10.34067/kid.0003782020] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 09/02/2020] [Indexed: 04/27/2023]
Abstract
The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, is crucial in regulating cell growth, metabolism, proliferation, and survival. Under physiologic conditions, mTOR signaling maintains podocyte and tubular cell homeostasis. In AKI, activation of mTOR signaling in tubular cells and interstitial fibroblasts promotes renal regeneration and repair. However, constitutive activation of mTOR signaling in kidneys results in the initiation and progression of glomerular hypertrophy, interstitial fibrosis, polycystic kidney disease, and renal cell carcinoma. Here, we summarize the recent studies about mTOR signaling in renal physiology and injury, and discuss the possibility of its use as a therapeutic target for kidney diseases.
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Affiliation(s)
- Yuan Gui
- Department of Nephrology, University of Connecticut Health Center, Farmington, Connecticut
| | - Chunsun Dai
- Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
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25
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Sakuma H, Hagiwara S, Kantharidis P, Gohda T, Suzuki Y. Potential Targeting of Renal Fibrosis in Diabetic Kidney Disease Using MicroRNAs. Front Pharmacol 2020; 11:587689. [PMID: 33364960 PMCID: PMC7751689 DOI: 10.3389/fphar.2020.587689] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major health problem and one of the leading causes of end-stage renal disease worldwide. Despite recent advances, there exists an urgent need for the development of new treatments for DKD. DKD is characterized by the excessive synthesis and deposition of extracellular matrix proteins in glomeruli and the tubulointerstitium, ultimately leading to glomerulosclerosis as well as interstitial fibrosis. Renal fibrosis is the final common pathway at the histological level leading to an end-stage renal failure. In fact, activation of the nuclear factor erythroid 2-related factor 2 pathway by bardoxolone methyl and inhibition of transforming growth factor beta signaling by pirfenidone have been assumed to be effective therapeutic targets for DKD, and various basic and clinical studies are currently ongoing. MicroRNAs (miRNAs) are endogenously produced small RNA molecules of 18–22 nucleotides in length, which act as posttranscriptional repressors of gene expression. Studies have demonstrated that several miRNAs contribute to renal fibrosis. In this review, we outline the potential of using miRNAs as an antifibrosis treatment strategy and discuss their clinical application in DKD.
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Affiliation(s)
- Hiroko Sakuma
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Shinji Hagiwara
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan.,Department of Kidney and Hypertension, Juntendo Tokyo Koto Geriatric Medical Center, Tokyo, Japan
| | | | - Tomohito Gohda
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
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Maity S, Das F, Kasinath BS, Ghosh-Choudhury N, Ghosh Choudhury G. TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression. J Biol Chem 2020; 295:14262-14278. [PMID: 32732288 DOI: 10.1074/jbc.ra120.014994] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 07/27/2020] [Indexed: 12/21/2022] Open
Abstract
Interaction of transforming growth factor-β (TGFβ)-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of the TGFβ receptor involved in the noncanonical signaling is unknown. Here, we show that TGFβ increased the catalytic loop phosphorylation of platelet-derived growth factor receptor β (PDGFRβ), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFβ increased phosphorylation of the PI 3-kinase-interacting Tyr-751 residue of PDGFRβ, thus activating Akt. Inhibition of PDGFRβ using a pharmacological inhibitor and siRNAs blocked TGFβ-stimulated phosphorylation of proline-rich Akt substrate of 40 kDa (PRAS40), an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active myristoylated Akt reversed the siPDGFRβ-mediated inhibition of mTORC1 activity; however, co-expression of the phospho-deficient mutant of PRAS40 inhibited the effect of myristoylated Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRβ in mesangial cells. Additionally, we demonstrate that PDGFRβ-initiated phosphorylation of PRAS40 is required for TGFβ-induced mesangial cell hypertrophy and fibronectin and collagen I (α2) production. Increased activating phosphorylation of PDGFRβ is also associated with enhanced TGFβ expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rats, respectively. Thus, pursuing TGFβ noncanonical signaling, we identified how TGFβ receptor I achieves mTORC1 activation through PDGFRβ-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRβ in TGFβ-driven renal fibrosis.
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Affiliation(s)
- Soumya Maity
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Falguni Das
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Balakuntalam S Kasinath
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA.,Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA
| | | | - Goutam Ghosh Choudhury
- Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA .,Department of Veterans Affairs Research, South Texas Veterans Health Care System, San Antonio, Texas, USA.,Geriatric Research, Education, and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, USA
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27
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Hu G, Xia Y, Zhang J, Chen Y, Yuan J, Niu X, Zhao B, Li Q, Wang Y, Deng Z. ESC-sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2020; 7:1903330. [PMID: 32440476 PMCID: PMC7237844 DOI: 10.1002/advs.201903330] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 02/20/2020] [Accepted: 02/24/2020] [Indexed: 05/05/2023]
Abstract
Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time-related increasing in hippocampal neural stem cells (H-NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell-derived small extracellular vesicles (ESC-sEVs) are intravenously injected into VD rats. ESC-sEVs treatment significantly alleviates H-NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT-qPCR it is identified that several miRNAs including miR-17-5p, miR-18a-5p, miR-21-5p, miR-29a-3p, and let-7a-5p, that can inhibit mTORC1 activation, exist in ESC-sEVs. ESC-sEVs rejuvenate H-NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB (TFEB) nuclear translocation and lysosome resumption. Taken together, these data indicate that H-NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC-sEVs treatment ameliorates H-NSCs senescence by inhibiting mTORC1 activation, and promoting TFEB nuclear translocation and lysosome resumption, thereby reversing senescence-related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC-sEVs may be a novel cell-free therapeutic tool for patients with VD, as well as other aging-related diseases.
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Affiliation(s)
- Guowen Hu
- Department of NeurosurgeryShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Yuguo Xia
- Department of NeurosurgeryShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Juntao Zhang
- Institute of Microsurgery on ExtremitiesShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Yu Chen
- Institute of Microsurgery on ExtremitiesShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Ji Yuan
- Institute of Microsurgery on ExtremitiesShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Xin Niu
- Institute of Microsurgery on ExtremitiesShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Bizeng Zhao
- Department of Orthopedic SurgeryShanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200233China
| | - Qing Li
- Institute of Microsurgery on ExtremitiesShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Yang Wang
- Institute of Microsurgery on ExtremitiesShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
| | - Zhifeng Deng
- Department of NeurosurgeryShanghai Jiaotong University Affiliated Sixth People's HospitalShanghai200233China
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Abstract
Cardiac hypertrophy is a significant risk factor for cardiovascular disease, including heart failure, arrhythmia, and sudden death. Cardiac hypertrophy involves both embryonic gene expression and transcriptional reprogramming, which are tightly regulated by epigenetic mechanisms. An increasing number of studies have demonstrated that epigenetics plays an influential role in the occurrence and development of cardiac hypertrophy. Here, we summarize the latest research progress on epigenetics in cardiac hypertrophy involving DNA methylation, histone modification, and non-coding RNA, to help understand the mechanism of epigenetics in cardiac hypertrophy. The expression of both embryonic and functional genes can be precisely regulated by epigenetic mechanisms during cardiac hypertrophy, providing a substantial number of therapeutic targets. Thus, epigenetic treatment is expected to become a novel therapeutic strategy for cardiac hypertrophy. According to the research performed to date, epigenetic mechanisms associated with cardiac hypertrophy remain far from completely understood. Therefore, epigenetic mechanisms require further exploration to improve the prevention, diagnosis, and treatment of cardiac hypertrophy.
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Affiliation(s)
- Hao Lei
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Jiahui Hu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Kaijun Sun
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China
| | - Danyan Xu
- Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha, 410011, Hunan, China.
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Urinary MicroRNA-21-5p as Potential Biomarker of Interstitial Fibrosis and Tubular Atrophy (IFTA) in Kidney Transplant Recipients. Diagnostics (Basel) 2020; 10:diagnostics10020113. [PMID: 32092939 PMCID: PMC7168003 DOI: 10.3390/diagnostics10020113] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 02/11/2020] [Accepted: 02/17/2020] [Indexed: 12/29/2022] Open
Abstract
Chronic renal allograft dysfunction (CAD) is a major limiting factor of long-term graft survival. The hallmarks of progressive CAD are interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs are small, regulatory RNAs involved in many immunological processes. In particular, microRNA-21-5p (miR-21) is considered to be strongly associated with pathogenesis regarding tubulointerstitium. The aim of this study was to assess urinary miR-21 expression levels in the kidney transplant recipients and determine their application in the evaluation of IFTA and kidney allograft function. The expression levels of miR-21 were quantified in the urine of 31 kidney transplant recipients with biopsy-assessed IFTA (IFTA 0 + I: n = 17; IFTA II + III: n = 14) by real-time quantitative PCR. Urine samples were collected at the time of protocolar biopsies performed 1 or 2 years after kidney transplantation. MicroRNA-191-5p was used as reference gene. MiR-21 was significantly up-regulated in IFTA II + III group compared to IFTA 0 + I group (p = 0.003). MiR-21 correlated significantly with serum concentration of creatinine (r = 0.52, p = 0.003) and eGFR (r = -0.45; p = 0.01). ROC analysis determined the diagnostic value of miR-21 with an area under curve (AUC) of 0.80 (p = 0.0002), sensitivity of 0.86 and specificity of 0.71. miR-21 is associated with renal allograft dysfunction and IFTA. Therefore, it could be considered as a potential diagnostic, non-invasive biomarker for monitoring renal graft function.
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30
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Tang J, Goldschmeding R, Samarakoon R, Higgins PJ. Protein phosphatase Mg 2+ /Mn 2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression. FASEB J 2019; 34:2641-2656. [PMID: 31909517 DOI: 10.1096/fj.201902015rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/20/2019] [Accepted: 12/05/2019] [Indexed: 12/17/2022]
Abstract
PPM1A and PTEN emerged as novel suppressors of chronic kidney disease (CKD). Since loss of PPM1A and PTEN in the tubulointerstitium promotes fibrogenesis, defining molecular events underlying PPM1A/PTEN deregulation is necessary to develop expression rescue as novel therapeutic strategies. Here we identify TGF-β1 as a principle repressor of PPM1A, as conditional renal tubular-specific induction of TGF-β1 in mice dramatically downregulates kidney PPM1A expression. TGF-β1 similarly attenuates PPM1A and PTEN expression in human renal epithelial cells and fibroblasts, via a protein degradation mechanism by promoting their ubiquitination. A proteasome inhibitor MG132 rescues PPM1A and PTEN expression, even in the presence of TGF-β1, along with decreased fibrogenesis. Restoration of PPM1A or PTEN similarly limits SMAD3 phosphorylation and the activation of TGF-β1-induced fibrotic genes. Concurrent loss of PPM1A and PTEN levels in aristolochic acid nephropathy further suggests crosstalk between these repressors. PPM1A silencing in renal fibroblasts, moreover, results in PTEN loss, while PTEN stable depletion decreases PPM1A expression with acquisition of a fibroproliferative phenotype in each case. Transient PPM1A expression, conversely, elevates cellular PTEN levels while lentiviral PTEN introduction increases PPM1A expression. PPM1A and PTEN, therefore, co-regulate each other's relative abundance, identifying a previously unknown pathological link between TGF-β1 repressors, contributing to CKD.
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Affiliation(s)
- Jiaqi Tang
- Department of Regenerative and Cancer Cell Biology, Albany Medical Center, Albany, NY, USA
| | - Roel Goldschmeding
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Rohan Samarakoon
- Department of Regenerative and Cancer Cell Biology, Albany Medical Center, Albany, NY, USA
| | - Paul J Higgins
- Department of Regenerative and Cancer Cell Biology, Albany Medical Center, Albany, NY, USA
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31
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FOXP1 inhibits high glucose-induced ECM accumulation and oxidative stress in mesangial cells. Chem Biol Interact 2019; 313:108818. [DOI: 10.1016/j.cbi.2019.108818] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/12/2019] [Accepted: 09/05/2019] [Indexed: 01/09/2023]
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Liu B, Zhang J, Yang D. miR-96-5p promotes the proliferation and migration of ovarian cancer cells by suppressing Caveolae1. J Ovarian Res 2019; 12:57. [PMID: 31228941 PMCID: PMC6588920 DOI: 10.1186/s13048-019-0533-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/12/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ovarian cancer (OC) is the second most common gynaecological malignancy. MicroRNAs (miRNAs) have been found to be aberrantly expressed in OC tissue and have been proposed as biomarkers and therapeutic targets for OC. RESULTS In this study, we found that miR-96-5p was up-regulated in OC tissues and OC cells compared to normal ovarian tissues and epithelial cell line. And, miR-96-5p was also up-regulated in the serum samples from OC patients compared to health participants. In addition, there was a positive correlation of miR-96-5p levels between OC tissues and serum samples. At the cellular level, overexpression of miR-96-5p promoted cell proliferation and migration in OC cells. Moreover, we further validated Caveolae1 (CAV1) as the direct target of miR-96-5p in OC cells through luciferase activity assays and western blot. CAV1 was obvious low expression in OC tissues. The overexpression of CAV1 abrogated the promotion of miR-96-5p on the OC cells proliferation and migration. Finally, we found that AKT signaling pathway was involved in this process. MiR-96-5p inhibited the phosphorylation of AKT and expression of down-stream proteins Cyclin D1 and P70 by targeting CAV1. CONCLUSIONS The above findings suggested that targeting miR-96-5p may be a promising strategy for OC treatment.
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Affiliation(s)
- Bo Liu
- Department of gynaecology & obstetrics, Jinan Maternal & Children Health Care Hospital, No 2 Jianguo Xiaojing Three road, Jinan, 250001, Shandong, People's Republic of China
| | - Jinglu Zhang
- Department of gynaecology & obstetrics, Jinan Maternal & Children Health Care Hospital, No 2 Jianguo Xiaojing Three road, Jinan, 250001, Shandong, People's Republic of China
| | - Dongxia Yang
- Department of gynaecology & obstetrics, Jinan Maternal & Children Health Care Hospital, No 2 Jianguo Xiaojing Three road, Jinan, 250001, Shandong, People's Republic of China.
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Ming L, Ning J, Ge Y, Zhang Y, Ruan Z. Excessive apoptosis of podocytes caused by dysregulation of microRNA-182-5p and CD2AP confers to an increased risk of diabetic nephropathy. J Cell Biochem 2019; 120:16516-16523. [PMID: 31131477 DOI: 10.1002/jcb.28911] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 03/08/2019] [Accepted: 03/15/2019] [Indexed: 01/28/2023]
Abstract
The functions of miR-182-5p in the pathogenesis of diabetic nephropathy (DN) remain largely unclear. Here, we studied the roles and relationship between miR-182-5p and CD2AP in the development of DN. We used real-time polymerase chain reaction (PCR) to compare miR-182-5p expression between DN and control groups, while computational analysis and luciferase assays were used to confirm CD2AP as a miR-182-5p target. Western blot and real-time PCR were then used to measure the messenger RNA (mRNA) and protein expression of CD2AP in the presence of miR-182-5p. The results showed that miR-182-5p was highly expressed in cells isolated from people with DN. In addition, the luciferase activity of cells transfected with wild-type/mutant CD2AP confirmed CD2AP as a direct target of miR-182-5p. The expression levels of CD2AP mRNA and protein were much lower in the DN group compared with that in the normal group. In addition, the expression levels of CD2AP mRNA and protein were evidently increased by a miR-182-5p inhibitor, but notably downregulated by miR-182-5p mimics or CD2AP small interfering RNA (siRNA). Furthermore, miR-182-5p and CD2Ap siRNA significantly reduced the survival rate and viability of transfected cells, while the miR-182-5p inhibitor exhibited an opposite effect. These findings indicated the presence of a negative regulatory relationship between miR-182-5p and CD2AP in podocytes cells and suggested that the overexpression of miR-182-5p contributes to the pathogenesis of DN.
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Affiliation(s)
- Lei Ming
- Department of Image, Shandong Qianfoshan Hospital, Jinan, Shandong, China
| | - Jing Ning
- Nursing Department, Wucheng People's Hospital, Dezhou, Shandong, China
| | - Yuan Ge
- Department of Anesthesiology, Jinan Central Hospital, Jinan, Shandong, China
| | - Ying Zhang
- Department of Nephrology, Shandong Qianfoshan Hospital, Jinan, Shandong, China
| | - Zhen Ruan
- Department of Tumor Chemotherapy, Shandong Qianfoshan Hospital, Jinan, Shandong, China
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Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis. Int J Mol Sci 2019; 20:ijms20081977. [PMID: 31018516 PMCID: PMC6515288 DOI: 10.3390/ijms20081977] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/19/2019] [Accepted: 04/20/2019] [Indexed: 12/15/2022] Open
Abstract
Fibrosis, or tissue scarring, is defined as the excessive, persistent and destructive accumulation of extracellular matrix components in response to chronic tissue injury. Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function. Limited therapeutic options are available and the molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the role of non-coding RNAs, and in particular microRNAs (miRNAs), has been described in kidney fibrosis. Seminal studies have highlighted their potential importance as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review will summarize recent scientific advances and will discuss potential clinical applications as well as future research directions.
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Sandbo N. Mechanisms of Fibrosis in IPF. Respir Med 2019. [DOI: 10.1007/978-3-319-99975-3_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
The main cellular constituents in glomerular mesangium are mesangial cells, which account for approximately 30-40% of the total cells in the glomerulus. Together with the mesangial matrix, mesangial cells form the glomerular basement membrane (GBM) in the glomerulus, whose main function is to perform the filtration. Under the pathologic conditions, mesangial cells are activated, leading to hyperproliferation and excess extracellular matrix (ECM). Moreover, mesangial cells also secrete several kinds of inflammatory cytokines, adhesion molecules, chemokines, and enzymes, all of which participate in the process of renal glomerular fibrosis. During the past years, researchers have revealed the roles of mesangial cells and the associated signal pathways involved in renal fibrosis. In this section, we will discuss how mesangial cells are activated and its contributions to renal fibrosis, as well as the molecular mechanisms and novel anti-fibrotic agents. Full understanding of the contributions of mesangial cells to renal fibrosis will benefit the clinical drug developing.
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Affiliation(s)
- Jing-Hong Zhao
- Department of Nephrology, Xinqiao Hospital, Army Medical University, Chongqing, China.
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TGF-β Family Signaling Pathways in Cellular Dormancy. Trends Cancer 2018; 5:66-78. [PMID: 30616757 DOI: 10.1016/j.trecan.2018.10.010] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 10/16/2018] [Accepted: 10/30/2018] [Indexed: 02/07/2023]
Abstract
Individual cancer cells can switch, reversibly, to a non-proliferative dormant state, a process characterized by two principal stages: (i) establishment and maintenance, and (ii) the breaking of dormancy. This phenomenon is of clinical importance because dormant cells resist chemotherapy, and this can result in cancer relapse following years, if not decades, of clinical remission. Although the molecular mechanisms governing tumor cell dormancy have not been clearly delineated, accumulating evidence suggests that members of the transforming growth factor-β (TGF-β) family are integral. We summarize here recent findings which support the view that TGF-β family signaling pathways play a pivotal role in cellular dormancy, and discuss how affected cells could be therapeutically targeted to prevent cancer relapse.
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Akt2 causes TGFβ-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression. PLoS One 2018; 13:e0207285. [PMID: 30444896 PMCID: PMC6239304 DOI: 10.1371/journal.pone.0207285] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 10/29/2018] [Indexed: 02/06/2023] Open
Abstract
TGFβ promotes podocyte hypertrophy and expression of matrix proteins in fibrotic kidney diseases such as diabetic nephropathy. Both mTORC1 and mTORC2 are hyperactive in response to TGFβ in various renal diseases. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. We identified that deptor downregulation by TGFβ maintains hyperactive mTOR in podocytes. To unravel the mechanism, we found that TGFβ -initiated noncanonical signaling controls deptor inhibition. Pharmacological inhibitor of PI 3 kinase, Ly 294002 and pan Akt kinase inhibitor MK 2206 prevented the TGFβ induced downregulation of deptor, resulting in suppression of both mTORC1 and mTORC2 activities. However, specific isoform of Akt involved in this process is not known. We identified Akt2 as predominant isoform expressed in kidney cortex, glomeruli and podocytes. TGFβ time-dependently increased the activating phosphorylation of Akt2. Expression of dominant negative PI 3 kinase and its signaling inhibitor PTEN blocked Akt2 phosphorylation by TGFβ. Inhibition of Akt2 using a phospho-deficient mutant that inactivates its kinase activity, as well as siRNA against the kinase markedly diminished TGFβ -mediated deptor suppression, its association with mTOR and activation of mTORC1 and mTORC2. Importantly, inhibition of Akt2 blocked TGFβ -induced podocyte hypertrophy and expression of the matrix protein fibronectin. This inhibition was reversed by the downregulation of deptor. Interestingly, we detected increased phosphorylation of Akt2 concomitant with TGFβ expression in the kidneys of diabetic rats. Thus, our data identify previously unrecognized Akt2 kinase as a driver of TGFβ induced deptor downregulation and sustained mTORC1 and mTORC2 activation. Furthermore, we provide the first evidence that deptor downstream of Akt2 contributes to podocyte hypertrophy and matrix protein expression found in glomerulosclerosis in different renal diseases.
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39
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Guo S. Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis. Reprod Med Biol 2018; 17:369-397. [PMID: 30377392 PMCID: PMC6194252 DOI: 10.1002/rmb2.12221] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/03/2018] [Accepted: 06/24/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND One recent study reports cancer driver mutations in deep endometriosis, but its biological/clinical significance remains unclear. Since the natural history of endometriosis is essentially gradual progression toward fibrosis, it is thus hypothesized that the six driver genes reported to be mutated in endometriosis (the RP set) may play important roles in fibrogenesis but not necessarily malignant transformation. METHODS Extensive PubMed search to see whether RP and another set of driver genes not yet reported (NR) to be mutated in endometriosis have any roles in fibrogenesis. All studies reporting on the role of fibrogenesis of the genes in both RP and NR sets were retrieved and evaluated in this review. RESULTS All six RP genes were involved in various aspects of fibrogenesis as compared with only three NR genes. These nine genes can be anchored in networks linking with their upstream and downstream genes that are known to be aberrantly expressed in endometriosis, piecing together seemingly unrelated findings. CONCLUSIONS Given that somatic driver mutations can and do occur frequently in physiologically normal tissues, it is argued that these mutations in endometriosis are not necessarily synonymous with malignancy or premalignancy, but the result of enormous pressure for fibrogenesis.
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Affiliation(s)
- Sun‐Wei Guo
- Shanghai Obstetrics and Gynecology HospitalFudan UniversityShanghaiChina
- Shanghai Key Laboratory of Female Reproductive Endocrine‐Related DiseasesShanghaiChina
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40
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Kato M. Noncoding RNAs as therapeutic targets in early stage diabetic kidney disease. Kidney Res Clin Pract 2018; 37:197-209. [PMID: 30254844 PMCID: PMC6147183 DOI: 10.23876/j.krcp.2018.37.3.197] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2018] [Revised: 07/18/2018] [Accepted: 07/18/2018] [Indexed: 02/01/2023] Open
Abstract
Diabetic kidney disease (DKD) is a major renal complication of diabetes that leads to renal dysfunction and end-stage renal disease (ESRD). Major features of DKD include accumulation of extracellular matrix proteins and glomerular hypertrophy, especially in early stage. Transforming growth factor-β plays key roles in regulation of profibrotic genes and signal transducers such as Akt kinase and MAPK as well as endoplasmic reticulum stress, oxidant stress, and autophagy related to hypertrophy in diabetes. Many drugs targeting the pathogenic signaling in DKD (mostly through protein-coding genes) are under development. However, because of the limited number of protein-coding genes, noncoding RNAs (ncRNAs) including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are attracting more attention as potential new drug targets for human diseases. Some miRNAs and lncRNAs regulate each other (by hosting, enhancing transcription from the neighbor, hybridizing each other, and changing chromatin modifications) and create circuits and cascades enhancing the pathogenic signaling in DKD. In this short and focused review, the functional significance of ncRNAs (miRNAs and lncRNAs) in the early stages of DKD and their therapeutic potential are discussed.
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Affiliation(s)
- Mitsuo Kato
- Beckman Research Institute of City of Hope, Duarte, CA, USA
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41
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Rackov G, Garcia-Romero N, Esteban-Rubio S, Carrión-Navarro J, Belda-Iniesta C, Ayuso-Sacido A. Vesicle-Mediated Control of Cell Function: The Role of Extracellular Matrix and Microenvironment. Front Physiol 2018; 9:651. [PMID: 29922170 PMCID: PMC5996101 DOI: 10.3389/fphys.2018.00651] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 05/14/2018] [Indexed: 12/20/2022] Open
Abstract
Extracellular vesicles (EVs) — including exosomes, microvesicles and apoptotic bodies — have received much scientific attention last decade as mediators of a newly discovered cell-to-cell communication system, acting at short and long distances. EVs carry biologically active molecules, thus providing signals that influence a spectrum of functions in recipient cells during various physiological and pathological processes. Recent findings point to EVs as very attractive immunomodulatory therapeutic agents, vehicles for drug delivery and diagnostic and prognostic biomarkers in liquid biopsies. In addition, EVs interact with and regulate the synthesis of extracellular matrix (ECM) components, which is crucial for organ development and wound healing, as well as bone and cardiovascular calcification. EVs carrying matrix metalloproteinases (MMPs) are involved in ECM remodeling, thus modifying tumor microenvironment and contributing to premetastatic niche formation and angiogenesis. Here we review the role of EVs in control of cell function, with emphasis on their interaction with ECM and microenvironment in health and disease.
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Affiliation(s)
| | | | - Susana Esteban-Rubio
- Fundación de Investigación HM Hospitales, Madrid, Spain.,Facultad de Medicina (IMMA), Universidad CEU San Pablo, Madrid, Spain
| | | | | | - Angel Ayuso-Sacido
- IMDEA Nanoscience Institute, Madrid, Spain.,Fundación de Investigación HM Hospitales, Madrid, Spain.,Facultad de Medicina (IMMA), Universidad CEU San Pablo, Madrid, Spain
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42
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Jin H, Li DY, Chernogubova E, Sun C, Busch A, Eken SM, Saliba-Gustafsson P, Winter H, Winski G, Raaz U, Schellinger IN, Simon N, Hegenloh R, Matic LP, Jagodic M, Ehrenborg E, Pelisek J, Eckstein HH, Hedin U, Backlund A, Maegdefessel L. Local Delivery of miR-21 Stabilizes Fibrous Caps in Vulnerable Atherosclerotic Lesions. Mol Ther 2018; 26:1040-1055. [PMID: 29503197 PMCID: PMC6080193 DOI: 10.1016/j.ymthe.2018.01.011] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 01/08/2018] [Accepted: 01/12/2018] [Indexed: 01/22/2023] Open
Abstract
miRNAs are potential regulators of carotid artery stenosis and concordant vulnerable atherosclerotic plaques. Hence, we analyzed miRNA expression in laser captured micro-dissected fibrous caps of either ruptured or stable plaques (n = 10 each), discovering that miR-21 was significantly downregulated in unstable lesions. To functionally evaluate miR-21 in plaque vulnerability, miR-21 and miR-21/apolipoprotein-E double-deficient mice (Apoe-/-miR-21-/-) were assessed. miR-21-/- mice lacked sufficient smooth muscle cell proliferation in response to carotid ligation injury. When exposing Apoe-/-miR-21-/- mice to an inducible plaque rupture model, they presented with more atherothrombotic events (93%) compared with miR-21+/+Apoe-/- mice (57%). We discovered that smooth muscle cell fate in experimentally induced advanced lesions is steered via a REST-miR-21-REST feedback signaling pathway. Furthermore, Apoe-/-miR-21-/- mice presented with more pronounced atherosclerotic lesions, greater foam cell formation, and substantially higher levels of arterial macrophage infiltration. Local delivery of a miR-21 mimic using ultrasound-targeted microbubbles into carotid plaques rescued the vulnerable plaque rupture phenotype. In the present study, we identify miR-21 as a key modulator of pathologic processes in advanced atherosclerosis. Targeted, lesion site-specific overexpression of miR-21 can stabilize vulnerable plaques.
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Affiliation(s)
- Hong Jin
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Daniel Y Li
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Munich, Germany
| | | | - Changyan Sun
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Albert Busch
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Munich, Germany
| | - Suzanne M Eken
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | | | - Hanna Winter
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Greg Winski
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Uwe Raaz
- University Heart Center, Göttingen, Germany
| | | | - Nancy Simon
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Renate Hegenloh
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Munich, Germany
| | - Ljubica Perisic Matic
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Maja Jagodic
- Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden
| | - Ewa Ehrenborg
- Department of Medicine, Karolinska Institute, Stockholm, Sweden
| | - Jaroslav Pelisek
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Munich, Germany
| | - Hans-Henning Eckstein
- Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Munich, Germany
| | - Ulf Hedin
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | | | - Lars Maegdefessel
- Department of Medicine, Karolinska Institute, Stockholm, Sweden; Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany; German Center for Cardiovascular Research (DZHK), Munich, Germany.
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43
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Benway CJ, Iacomini J. Defining a microRNA-mRNA interaction map for calcineurin inhibitor induced nephrotoxicity. Am J Transplant 2018; 18:796-809. [PMID: 28925592 DOI: 10.1111/ajt.14503] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Revised: 08/21/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023]
Abstract
Calcineurin inhibitors induce nephrotoxicity through poorly understood mechanisms thereby limiting their use in transplantation and other diseases. Here we define a microRNA (miRNA)-messenger RNA (mRNA) interaction map that facilitates exploration into the role of miRNAs in cyclosporine-induced nephrotoxicity (CIN) and the gene pathways they regulate. Using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we isolated RNAs associated with Argonaute 2 in the RNA-induced silencing complex (RISC) of cyclosporine A (CsA) treated and control human proximal tubule cells and identified mRNAs undergoing active targeting by miRNAs. CsA causes specific changes in miRNAs and mRNAs associated with RISC, thereby altering post-transcriptional regulation of gene expression. Pathway enrichment analysis identified canonical pathways regulated by miRNAs specifically following CsA treatment. RNA-seq performed on total RNA indicated that only a fraction of total miRNAs and mRNAs are actively targeted in the RISC, indicating that PAR-CLIP more accurately defines meaningful targeting interactions. Our data also revealed a role for miRNAs in calcineurin-independent regulation of JNK and p38 MAPKs caused by targeting of MAP3K1. Together, our data provide a novel resource and unique insights into molecular pathways regulated by miRNAs in CIN. The gene pathways and miRNAs defined may represent novel targets to reduce calcineurin induced nephrotoxicity.
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Affiliation(s)
- Christopher J Benway
- Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.,Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA
| | - John Iacomini
- Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA.,Graduate Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.,Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, USA.,Tufts University School of Medicine, Boston, MA, USA
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Maity S, Bera A, Ghosh-Choudhury N, Das F, Kasinath BS, Choudhury GG. microRNA-181a downregulates deptor for TGFβ-induced glomerular mesangial cell hypertrophy and matrix protein expression. Exp Cell Res 2018; 364:5-15. [PMID: 29397070 DOI: 10.1016/j.yexcr.2018.01.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 01/16/2018] [Indexed: 02/06/2023]
Abstract
TGFβ contributes to mesangial cell hypertrophy and matrix protein increase in various kidney diseases including diabetic nephropathy. Deptor is an mTOR-interacting protein and suppresses mTORC1 and mTORC2 activities. We have recently shown that TGFβ-induced inhibition of deptor increases the mTOR activity. The mechanism by which TGFβ regulates deptor expression is not known. Here we identify deptor as a target of the microRNA-181a. We show that in mesangial cells, TGFβ increases the expression of miR-181a to downregulate deptor. Decrease in deptor augments mTORC2 activity, resulting in phosphorylation/activation of Akt kinase. Akt promotes inactivating phosphorylation of PRAS40 and tuberin, leading to stimulation of mTORC1. miR-181a-mimic increased mTORC1 and C2 activities, while anti-miR-181a inhibited them. mTORC1 controls protein synthesis via phosphorylation of translation initiation and elongation suppressors 4EBP-1 and eEF2 kinase. TGFβ-stimulated miR-181a increased the phosphorylation of 4EBP-1 and eEF2 kinase, resulting in their inactivation. miR-181a-dependent inactivation of eEF2 kinase caused dephosphorylation of eEF2. Consequently, miR-181a-mimic increased protein synthesis and hypertrophy of mesangial cells similar to TGFβ. Anti-miR-181a blocked these events in a deptor-dependent manner. Finally, TGFβ-miR-181a-driven deptor downregulation increased the expression of fibronectin. Our results identify a novel mechanism involving miR-181a-driven deptor downregulation, which contributes to mesangial cell pathologies in renal complications.
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Affiliation(s)
- Soumya Maity
- Department of Medicine, UT Health San Antonio, TX, United States
| | - Amit Bera
- Department of Medicine, UT Health San Antonio, TX, United States
| | - Nandini Ghosh-Choudhury
- VA Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, TX, United States; Department of Pathology, UT Health San Antonio, TX, United States
| | - Falguni Das
- Department of Medicine, UT Health San Antonio, TX, United States; VA Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, TX, United States
| | - Balakuntalam S Kasinath
- Department of Medicine, UT Health San Antonio, TX, United States; VA Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, TX, United States
| | - Goutam Ghosh Choudhury
- Department of Medicine, UT Health San Antonio, TX, United States; VA Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, TX, United States; Geriatric Research, Education and Clinical Research Center, South Texas Veterans Health Care System, San Antonio, TX, United States.
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Tiwari D, Peariso K, Gross C. MicroRNA-induced silencing in epilepsy: Opportunities and challenges for clinical application. Dev Dyn 2018; 247:94-110. [PMID: 28850760 PMCID: PMC5740004 DOI: 10.1002/dvdy.24582] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 07/20/2017] [Accepted: 08/10/2017] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs are master regulators of gene expression. Single microRNAs influence multiple proteins within diverse molecular pathways and networks. Therefore, changes in levels or activity of microRNAs can have profound effects on cellular function. This makes dysregulated microRNA-induced silencing an attractive potential disease mechanism in complex disorders like epilepsy, where numerous cellular pathways and processes are affected simultaneously. Indeed, several years of research in rodent models have provided strong evidence that acute or recurrent seizures change microRNA expression and function. Moreover, altered microRNA expression has been observed in brain and blood from patients with various epilepsy disorders, such as tuberous sclerosis. MicroRNAs can be easily manipulated using sense or antisense oligonucleotides, opening up opportunities for therapeutic intervention. Here, we summarize studies using these techniques to identify microRNAs that modulate seizure susceptibility, describe protein targets mediating some of these effects, and discuss cellular pathways, for example neuroinflammation, that are controlled by epilepsy-associated microRNAs. We critically assess current gaps in knowledge regarding target- and cell-specificity of microRNAs that have to be addressed before clinical application as therapeutic targets or biomarkers. The recent progress in understanding microRNA function in epilepsy has generated strong momentum to encourage in-depth mechanistic studies to develop microRNA-targeted therapies. Developmental Dynamics 247:94-110, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Durgesh Tiwari
- Cincinnati Children’s Hospital Medical Center, Division of Neurology, Cincinnati, Ohio
| | - Katrina Peariso
- Cincinnati Children’s Hospital Medical Center, Division of Neurology, Cincinnati, Ohio
- University of Cincinnati, Department of Pediatrics, Cincinnati, Ohio
| | - Christina Gross
- Cincinnati Children’s Hospital Medical Center, Division of Neurology, Cincinnati, Ohio
- University of Cincinnati, Department of Pediatrics, Cincinnati, Ohio
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46
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Zhang Y, Zhao S, Wu D, Liu X, Shi M, Wang Y, Zhang F, Ding J, Xiao Y, Guo B. MicroRNA-22 Promotes Renal Tubulointerstitial Fibrosis by Targeting PTEN and Suppressing Autophagy in Diabetic Nephropathy. J Diabetes Res 2018; 2018:4728645. [PMID: 29850604 PMCID: PMC5903315 DOI: 10.1155/2018/4728645] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 01/03/2018] [Accepted: 01/14/2018] [Indexed: 12/11/2022] Open
Abstract
Renal tubulointerstitial fibrosis (TIF) is a major feature of diabetic nephropathy (DN). There is increasing evidence demonstrating that microRNAs act as key players in the regulation of autophagy and are involved in DN. However, the exact link among microRNAs, autophagy, and TIF in DN is largely unknown. In this study, our results showed that TIF was observed in DN rats together with obvious autophagy suppression. Moreover, microRNA-22 (miR-22) was upregulated and associated with reduced expression of its target gene phosphatase and tensin homolog (PTEN) in both the kidneys of DN rats and high glucose-cultured NRK-52E cells. Intriguingly, induction of autophagy by rapamycin antagonized high glucose-induced collagen IV (Col IV) and α-SMA expression. In addition, ectopic expression of miR-22 suppressed autophagic flux and induced the expression of Col IV and α-SMA, whereas the inhibition of endogenous miR-22 effectively relieved high glucose-induced autophagy suppression and the expression of Col IV and α-SMA in NRK-52E cells. Overexpression of PTEN protectively antagonized high glucose- and miR-22-induced autophagy suppression and the expression of Col IV. Therefore, our findings indicated that miR-22 may promote TIF by suppressing autophagy partially via targeting PTEN and represents a novel and promising therapeutic target for DN.
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Affiliation(s)
- Yingying Zhang
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Siqi Zhao
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Depei Wu
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Xingmei Liu
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Mingjun Shi
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Yuanyuan Wang
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Fan Zhang
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Jing Ding
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Ying Xiao
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
| | - Bing Guo
- Department of Pathophysiology, Guizhou Medical University, Guiyang, Guizhou 550025, China
- Laboratory of Pathogenesis Research, Drug Prevention and Treatment of Major Diseases, Guizhou Medical University, Guiyang, Guizhou 550025, China
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Lv W, Fan F, Wang Y, Gonzalez-Fernandez E, Wang C, Yang L, Booz GW, Roman RJ. Therapeutic potential of microRNAs for the treatment of renal fibrosis and CKD. Physiol Genomics 2017; 50:20-34. [PMID: 29127220 DOI: 10.1152/physiolgenomics.00039.2017] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Chronic kidney disease (CKD), defined as reduced glomerular filtration rate, is increasingly becoming a major public health issue. At the histological level, renal fibrosis is the final common pathway leading to end-stage renal disease, irrespective of the initial injury. According to this view, antifibrotic agents should slow or halt the progression of CKD. However, due to multiple overlapping pathways stimulating fibrosis, it has been difficult to develop antifibrotic drugs that delay or reverse the progression of CKD. MicroRNAs (miRNAs) are small noncoding RNA molecules, 18-22 nucleotides in length, that control many developmental and cellular processes as posttranscriptional regulators of gene expression. Emerging evidence suggests that miRNAs targeted against genes involved in renal fibrosis might be potential candidates for the development of antifibrotic therapies for CKD. This review will discuss some of the miRNAs, such as Let-7, miR-21,-29, -192, -200,-324, -132, -212, -30, -126, -433, -214, and -199a, that are implicated in renal fibrosis and the potential to exploit these molecular targets for the treatment of CKD.
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Affiliation(s)
- Wenshan Lv
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi.,Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University , Qingdao , China
| | - Fan Fan
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Yangang Wang
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University , Qingdao , China
| | - Ezekiel Gonzalez-Fernandez
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
| | - Chen Wang
- Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University , Qingdao , China
| | - Lili Yang
- West Coast Clinic of Affiliated Hospital of Qingdao University , Qingdao , China
| | - George W Booz
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi
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Bera A, Das F, Ghosh-Choudhury N, Mariappan MM, Kasinath BS, Ghosh Choudhury G. Reciprocal regulation of miR-214 and PTEN by high glucose regulates renal glomerular mesangial and proximal tubular epithelial cell hypertrophy and matrix expansion. Am J Physiol Cell Physiol 2017; 313:C430-C447. [PMID: 28701356 PMCID: PMC5668576 DOI: 10.1152/ajpcell.00081.2017] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 07/06/2017] [Accepted: 07/09/2017] [Indexed: 02/06/2023]
Abstract
Aberrant expression of microRNAs (miRs) contributes to diabetic renal complications, including renal hypertrophy and matrix protein accumulation. Reduced expression of phosphatase and tensin homolog (PTEN) by hyperglycemia contributes to these processes. We considered involvement of miR in the downregulation of PTEN. In the renal cortex of type 1 diabetic mice, we detected increased expression of miR-214 in association with decreased levels of PTEN and enhanced Akt phosphorylation and fibronectin expression. Mesangial and proximal tubular epithelial cells exposed to high glucose showed augmented expression of miR-214. Mutagenesis studies using 3'-UTR of PTEN in a reporter construct revealed PTEN as a direct target of miR-214, which controls its expression in both of these cells. Overexpression of miR-214 decreased the levels of PTEN and increased Akt activity similar to high glucose and lead to phosphorylation of its substrates glycogen synthase kinase-3β, PRAS40, and tuberin. In contrast, quenching of miR-214 inhibited high-glucose-induced Akt activation and its substrate phosphorylation; these changes were reversed by small interfering RNAs against PTEN. Importantly, respective expression of miR-214 or anti-miR-214 increased or decreased the mammalian target of rapamycin complex 1 (mTORC1) activity induced by high glucose. Furthermore, mTORC1 activity was controlled by miR-214-targeted PTEN via Akt activation. In addition, neutralization of high-glucose-stimulated miR-214 expression significantly inhibited cell hypertrophy and expression of the matrix protein fibronectin. Finally, the anti-miR-214-induced inhibition of these processes was reversed by the expression of constitutively active Akt kinase and hyperactive mTORC1. These results uncover a significant role of miR-214 in the activation of mTORC1 that contributes to high-glucose-induced mesangial and proximal tubular cell hypertrophy and fibronectin expression.
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Affiliation(s)
- Amit Bera
- Department of Medicine, UT Health San Antonio, San Antonio, Texas
| | - Falguni Das
- Department of Medicine, UT Health San Antonio, San Antonio, Texas
| | - Nandini Ghosh-Choudhury
- Veterans Affairs Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, Texas
- Department of Pathology, UT Health San Antonio, San Antonio, Texas; and
| | | | - Balakuntalam S Kasinath
- Department of Medicine, UT Health San Antonio, San Antonio, Texas
- Veterans Affairs Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, Texas
| | - Goutam Ghosh Choudhury
- Department of Medicine, UT Health San Antonio, San Antonio, Texas;
- Veterans Affairs Biomedical Laboratory Research, South Texas Veterans Health Care System, San Antonio, Texas
- Geriatric Research, Education and Clinical Research, South Texas Veterans Health Care System, San Antonio, Texas
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Dai X, Fang M, Li S, Yan Y, Zhong Y, Du B. miR-21 is involved in transforming growth factor β1-induced chemoresistance and invasion by targeting PTEN in breast cancer. Oncol Lett 2017; 14:6929-6936. [PMID: 29151919 DOI: 10.3892/ol.2017.7007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/07/2017] [Indexed: 12/12/2022] Open
Abstract
Transforming growth factor β1 (TGF-β1) has been associated with poor outcomes in patients with breast cancer. However, the functions and underlying molecular mechanisms of TGF-β1 in breast cancer remain unknown. Therefore, the present study aimed to identify the effects of components of the TGF-β/microRNA (miR-)21/phosphatase and tensin homolog (PTEN) signaling axis in breast cancer. TGF-β1 was identified to upregulate the expression of miR-21, and miR-21 was demonstrated to be significantly upregulated in breast cancer tissues compared with benign proliferative breast disease. In addition, the expression of miR-21 was significantly associated with increased TGF-β1 and clinical characteristics in patients, including tumor grade and lymph node metastasis (all P<0.05). Furthermore, in the breast cancer MCF-7 cell line, TGF-β1 was revealed to induce the expression of miR-21 in a dose- and time-dependent manner. The results of the present study additionally demonstrated that increased miR-21, in response to TGF-β1 signaling, was associated with tumor invasion and chemoresistance in vitro. In addition, suppression of PTEN was mediated by TGF-β1-induced expression of miR-21 in breast cancer cells and using a miR-21 inhibitor revitalized the expression of PTEN. The results of the present study explored the functions of TGF-β1-stimulated expression of miR-21 to suppress the PTEN axis, which promotes breast cancer progression and chemoresistance.
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Affiliation(s)
- Xiaomeng Dai
- Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Mao Fang
- Department of Pathology, School of Basic Medical Science, Guangzhou Medical University, Guangzhou, Guangdong 510436, P.R. China
| | - Shuang Li
- Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Yongrong Yan
- Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Ying Zhong
- Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Bin Du
- Department of Pathology, Medical School of Jinan University, Guangzhou, Guangdong 510632, P.R. China.,Division of Clinic Pathology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510632, P.R. China
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Liu F, Liu C, Hu X, Shang Y, Wu L. MicroRNA-21: A Positive Regulator for Optimal Production of Type I and Type III Interferon by Plasmacytoid Dendritic Cells. Front Immunol 2017; 8:947. [PMID: 28871250 PMCID: PMC5567078 DOI: 10.3389/fimmu.2017.00947] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 07/25/2017] [Indexed: 01/04/2023] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are the major producers of type I and type III interferons (IFNs) that play essential roles in host antiviral immunity. MicroRNAs (miRs) are small, noncoding RNAs that can modulate many immune processes. Although molecular regulation of type I IFN production by pDCs has been studied extensively, the regulation of type III IFN production has not been studied thoroughly, particularly at posttranscriptional level. We show here that miR-21 is an essential positive regulator for the production of both IFN-α and IFN-λ by pDCs and for promoting host defense against viral infection. miR-21 was markedly upregulated in toll-like receptor (TLR)-activated pDCs and was crucial for TLR7/9 ligand- or herpesvirus-induced production of IFN-α and IFN-λ by pDCs. miR-21-deficient pDCs produced significantly lower levels of IFN-α and IFN-λ on activation than those by wild-type pDCs. Impaired antiviral immune responses were also observed in miR-21-deficient mice. Mechanistically, we identified phosphatase and tensin homolog (PTEN) as the major target of miR-21 in pDCs, and miR-21 deficiency resulted in increased expression of PTEN that suppressed TLR-mediated activation of PI3K-Akt-mTOR signaling in pDCs. Hence, our findings provide evidence that miR-21 positively regulates both IFN-α and IFN-λ production and identify an important role for miR-21 in regulating the function of pDCs and in host antiviral immunity.
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Affiliation(s)
- Fang Liu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Chunxi Liu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Xiaoyu Hu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Yingli Shang
- College of Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Li Wu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China.,Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China
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