|
1
|
Gan L, Geng L, Li Q, Zhang L, Huang Y, Lin J, Ou S. Allicin Ameliorated High-glucose Peritoneal Dialysis Solution-induced Peritoneal Fibrosis in Rats via the JAK2/STAT3 Signaling Pathway. Cell Biochem Biophys 2025; 83:1847-1859. [PMID: 39448419 DOI: 10.1007/s12013-024-01593-2] [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] [Accepted: 10/09/2024] [Indexed: 10/26/2024]
Abstract
Peritoneal fibrosis (PF) is one of the most serious complications of peritoneal dialysis (PD) and is the greatest obstacle to the clinical application of PD. Chinese herbal monomers have been effective in the prevention and treatment of PF. The aim of this study was to observe the effect of allicin on PF in rats induced by high glucose and to investigate its molecular mechanism of action. A rat model of PF was established by using a 4.25% glucose-based standard peritoneal dialysis solution. The degree of peritoneal pathological damage was assessed by Hematoxylin and eosin (H&E) staining. Peritoneal collagen deposition was detected by Masson's trichrome staining. The levels of Interleukin-6 (IL-6), Tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β) and monocyte chemoattractant protein-1 (MCP-1) in the serum were measured by Enzyme Linked Immunosorbent Assay (ELISA). The expression levels of TGF-β, α-smooth muscle actin (α-SMA) and collagen I were examined by western blotting and immunohistochemistry. The protein expression levels and mRNA levels of E-cadherin, N-cadherin, vimentin, janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) in peritoneal tissue were determined by western blotting and qRT-PCR. TGF-β1 stimulated human peritoneal mesothelial cells (HPMCs), and the cells were treated with allicin and the JAK2/STAT3 pathway activator colivelin alone or in combination. A cell counting kit-8 (CCK-8) assay was used to measure cell viability. The role of JAK2/STAT3 in the effects of allicin was confirmed via in vitro mechanistic research by western blotting, wound healing assays and Transwell assays. Allicin relieves the inflammatory response by downregulating the levels of IL-1β, IL-6, MCP-1 and TNF-α. Furthermore, allicin decreased the expression of TGF-β, α-SMA and collagen I. Allicin also alleviated epithelial-to-mesenchymal transition (EMT), as specifically manifested by increased E-cadherin and reduced N-cadherin and vimentin. Further studies revealed that allicin reduced the protein levels of JAK2, STAT3, p-JAK2, and p-STAT3. The results of the cellular experiments verified the above results. The ability of allicin to inhibit fibrosis and the EMT process was significantly attenuated after HPMCs were treated with colivelin. Taken together, these findings suggest that allicin inhibits inflammation and EMT, thereby improving PF, and this protective effect may be achieved by inhibiting the JAK2/STAT3 signaling pathway.
Collapse
Affiliation(s)
- Linwang Gan
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China.
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China.
| | - Lei Geng
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
| | - Qiancheng Li
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Liling Zhang
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
| | - Yan Huang
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
| | - Jiaru Lin
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
| | - Santao Ou
- Department of Nephrology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, Sichuan, 646000, China
| |
Collapse
|
|
2
|
Yan S, Zhao Y, Yang Y, Liu B, Xu W, Ma Z, Yang Q. Progress of ADAM17 in Fibrosis-Related Diseases. Mediators Inflamm 2025; 2025:9999723. [PMID: 40224489 PMCID: PMC11986189 DOI: 10.1155/mi/9999723] [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: 07/27/2024] [Accepted: 01/09/2025] [Indexed: 04/15/2025] Open
Abstract
Fibrosis leads to structural damage and functional decline and is characterized by an accumulation of fibrous connective tissue and a reduction in parenchymal cells. Because of its extremely poor prognosis, organ fibrosis poses a significant economic burden. In order to prevent and treat fibrosis more effectively, potential mechanisms need to be investigated. A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound protein. It regulates intracellular signaling and membrane protein degradation. Fibrosis mediated by ADAM17 has been identified as an important contributor, although the specific relationship between its multiple regulatory functions and the pathogenesis is unclear. This article describes ADAM17 activation, function, and regulation, as well as the role of ADAM17 mediated fibrosis injury in kidney, liver, heart, lung, skin, endometrium, and retina. To develop new therapeutic approaches based on ADAM17 related signal pathways.
Collapse
Affiliation(s)
- Suyan Yan
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Yaqi Zhao
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China
| | - Yuyu Yang
- UCL School of Pharmacy, University College London, London, UK
| | - Baocheng Liu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Wei Xu
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China
| | - Zhenzhen Ma
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
- Shandong University of Traditional Chinese Medicine, Jinan 250021, Shandong, China
| | - Qingrui Yang
- Department of Rheumatology and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China
- Department of Rheumatology and Immunology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong, China
| |
Collapse
|
|
3
|
Feng R, Liu H, Chen Y. Baricitinib represses the myocardial fibrosis via blocking JAK/STAT and TGF-β1 pathways in vivo and in vitro. BMC Cardiovasc Disord 2025; 25:65. [PMID: 39891042 PMCID: PMC11783835 DOI: 10.1186/s12872-025-04517-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 01/22/2025] [Indexed: 02/03/2025] Open
Abstract
BACKGROUND JAK/STAT pathway is closely involved in the organ fibrotic process. The current study aimed to investigate the impact of baricitinib, an oral selective JAK1/JAK2 inhibitor, on the myocardial fibrosis in vivo and the activation of cardiac fibroblasts in vitro. METHODS The mouse myocardial fibrosis model was established by isoproterenol (ISO) treatment, then was treated by baricitinib. The activation of mouse cardiac fibroblasts was established by TGF-β1 stimulation, then was treated by baricitinib with several concentrations. Besides, JAK2 was knocked down by small interfering RNA (siRNA) in TGF-β1-stimulated mouse cardiac fibroblasts. RESULTS Baricitinib not only attenuated myocardial cell widening, inflammatory infiltration, fibrous tissue, and heart index, but also reduced collagen volume fraction, the expressions of Col1, Col3, α-SMA, Fn, MMP9, and TIMP1 in ISO-induced myocardial fibrosis mice. Meanwhile, baricitinib decreased the expressions of p-STAT3 and TGF-βRII in these mice. Interestingly, in TGF-β1-stimulated cardiac fibroblasts, baricitinib decreased the expressions of Col1, Col3, α-SMA, Fn, MMP9, and TIMP1 in a dose-dependent manner (From 10 to 2000 nM), also exhibited a dose-dependent impact on the expressions of p-STAT3 and TGF-βRII. Finally, JAK2 knockdown by siRNA downregulated the expressions of Col1, Col3, α-SMA, and Fn in TGF-β1-stimulated cardiac fibroblasts. CONCLUSION Inhibition of JAK/STAT pathway by baricitinib represses the myocardial fibrosis in vivo and in vitro, indicating baricitinib may be a treatment option for myocardial fibrosis, while further validation is needed.
Collapse
Affiliation(s)
- Renlei Feng
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
- Department of Geriatrics, Chongqing General Hospital, Chongqing University, Chongqing, 401147, China
| | - Hongli Liu
- Department of Geriatrics, Chongqing Medical University, Chongqing, 400016, China
| | - Yunqing Chen
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
| |
Collapse
|
|
4
|
Gu Y, Yu S, Gu W, Li B, Xue J, Liu J, Zhang Q, Yin Y, Zhang H, Guo Q, Yuan M, Lyu Z, Mu Y, Cheng Y. M2 macrophage infusion ameliorates diabetic glomerulopathy via the JAK2/STAT3 pathway in db/db mice. Ren Fail 2024; 46:2378210. [PMID: 39090966 PMCID: PMC11299449 DOI: 10.1080/0886022x.2024.2378210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/02/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
Objectives: To explore the therapeutic effects of M2 macrophages in diabetic nephropathy (DN) and their mechanism.Methods: We infused M2 macrophages stimulated with IL-4 into 10-week-old db/db mice once a week for 4 weeks through the tail vein as M2 group. Then we investigated the role of M2 macrophages in alleviating the infammation of DN and explored the mechanism.Results: M2 macrophages hindered the progression of DN, reduced the levels of IL-1β (DN group was 34%, M2 group was 13%, p < 0.01) and MCP-1 (DN group was 49%, M2 group was 16%, p < 0.01) in the glomeruli. It was also proven that M2 macrophages alleviate mesangial cell injury caused by a high glucose environment. M2 macrophage tracking showed that the infused M2 macrophages migrated to the kidney, and the number of M2 macrophages in the kidney reached a maximum on day 3. Moreover, the ratio of M2 to M1 macrophages was 2.3 in the M2 infusion group, while 0.4 in the DN group (p < 0.01). Mechanistically, M2 macrophages downregulated Janus kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3 in mesangial cells.Conclusions: Multiple infusions of M2 macrophages significantly alleviated inflammation in the kidney and hindered the progression of DN at least partially by abrogating the M1/M2 homeostasis disturbances and suppressing the JAK2/STAT3 pathway in glomerular mesangial cells. M2 macrophage infusion may be a new therapeutic strategy for DN treatment.
Collapse
Affiliation(s)
- Yulin Gu
- Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Songyan Yu
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Bing Li
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Jing Xue
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Jiejie Liu
- Department of Molecular Biology, Institute of Basic Medicine, School of Life Science, Chinese PLA General Hospital, Beijing, China
| | - Qi Zhang
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Haixia Zhang
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Qinghua Guo
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Mingxia Yuan
- Department of Endocrinology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhaohui Lyu
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Yiming Mu
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| | - Yu Cheng
- Department of Endocrinology, Medical School of Chinese PLA, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
5
|
Lahane GP, Dhar A, Bhat A. Therapeutic approaches and novel antifibrotic agents in renal fibrosis: A comprehensive review. J Biochem Mol Toxicol 2024; 38:e23795. [PMID: 39132761 DOI: 10.1002/jbt.23795] [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: 01/25/2024] [Revised: 06/20/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-β (TGF-β) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-β receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.
Collapse
Affiliation(s)
- Ganesh Panditrao Lahane
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Samba, Jammu and Kashmir, India
| |
Collapse
|
|
6
|
Li Q, Liu J, Su R, Zhen J, Liu X, Liu G. Small extracellular vesicles-shuttled miR-23a-3p from mesenchymal stem cells alleviate renal fibrosis and inflammation by inhibiting KLF3/STAT3 axis in diabetic kidney disease. Int Immunopharmacol 2024; 139:112667. [PMID: 39018690 DOI: 10.1016/j.intimp.2024.112667] [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: 03/26/2024] [Revised: 07/04/2024] [Accepted: 07/08/2024] [Indexed: 07/19/2024]
Abstract
Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) provide a pragmatic solution as a cell-free therapy for patients with diabetic kidney disease (DKD). However, the underlying protective mechanisms of MSC-sEV remain largely unknown in DKD. Invivo and in vitro analyses demonstrated that MSC-sEV attenuated renal fibrosis and inflammation of DKD. The underlying mechanism of the MSC-sEV-induced therapeutic effect was explored by high-throughput sequencing, which identified the unique enrichment of a set of miRNAs in MSC-sEV compared with human skin fibroblasts-sEV (HSF-sEV). Vitro experiments demonstrated that the protective potential was primarily attributed to miR-23a-3p, one of the most abundant miRNAs in MSC-sEV. Further, overexpression or knockdown analyses revealed that miR-23a-3p, and its target Krüppel-like factor 3 (KLF3) suppressed the STAT3 signaling pathway in high glucose (HG) induced HK-2 cells were essential for the renal-protective property of MSC-sEV. Moreover, we found that miR-23a-3p was packaged into MSC-sEV by RNA Binding Motif Protein X-Linked (RBMX) and transmitted to HG-induced HK-2 cells. Finally, inhibiting miR-23a-3p could mitigate the protective effects of MSC-sEV in db/db mice. These findings suggest that a systemic administration of sEV derived from MSC, have the capacity to incorporate into kidney where they can exert renal-protective potential against HG-induced injury through delivery of miR-23a-3p.
Collapse
Affiliation(s)
- Qianhua Li
- Nephrology Research Institute of Shandong University, Jinan, Shandong, 250033, China; Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Jiaxi Liu
- Graduate School of Arts and Sciences, Columbia University, USA
| | - Rongyun Su
- Nephrology Research Institute of Shandong University, Jinan, Shandong, 250033, China; Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Junhui Zhen
- Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China
| | - Xiangchun Liu
- Nephrology Research Institute of Shandong University, Jinan, Shandong, 250033, China; Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China
| | - Gang Liu
- Nephrology Research Institute of Shandong University, Jinan, Shandong, 250033, China; Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250033, China; Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong,250012, China.
| |
Collapse
|
|
7
|
Liu W, Zhang J, Zhang D, Zhang L. Role of circulating inflammatory protein in the development of diabetic renal complications: proteome-wide Mendelian randomization and colocalization analyses. Front Endocrinol (Lausanne) 2024; 15:1406442. [PMID: 39040677 PMCID: PMC11260607 DOI: 10.3389/fendo.2024.1406442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/13/2024] [Indexed: 07/24/2024] Open
Abstract
Background Diabetes ranks among the most widespread diseases globally, with the kidneys being particularly susceptible to its vascular complications. The identification of proteins for pathogenesis and novel drug targets remains imperative. This study aims to investigate roles of circulating inflammatory proteins in diabetic renal complications. Methods Data on the proteins were derived from a genome-wide protein quantitative trait locus (pQTL) study, while data on diabetic renal complications came from the FinnGen study. In this study, proteome-wide Mendelian randomization (MR) and colocalization analyses were used to assess the relationship between circulating inflammatory proteins and diabetic renal complications. Results MR approach indicated that elevated levels of interleukin 12B (IL-12B) (OR 1.691, 95%CI 1.179-2.427, P=4.34×10-3) and LIF interleukin 6 family cytokine (LIF) (OR 1.349, 95%CI 1.010-1.801, P=4.23×10-2) increased the risk of type 1 diabetes (T1D) with renal complications, while higher levels of fibroblast growth factor 19 (FGF19) (OR 1.202, 95%CI 1.009-1.432, P=3.93×10-2), fibroblast growth factor 23 (FGF23) (OR 1.379, 95%CI 1.035-1.837, P=2.82×10-2), C-C motif chemokine ligand 7 (CCL7) (OR 1.385, 95%CI 1.111-1.725, P=3.76×10-3), and TNF superfamily member 14 (TNFSF14) (OR 1.244, 95%CI 1.066-1.451, P=5.63×10-3) indicated potential risk factors for type 2 diabetes (T2D) with renal complications. Colocalization analysis supported these findings, revealing that most identified proteins, except for DNER, likely share causal variants with diabetic renal complications. Conclusion Our study established associations between specific circulating inflammatory proteins and the risk of diabetic renal complications, suggesting these proteins as targets for further investigation into the pathogenesis and potential therapeutic interventions for T1D and T2D with renal complications.
Collapse
Affiliation(s)
- Wenli Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jiaqi Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Duo Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lei Zhang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou, China
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
- Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
8
|
Wei Y, Wang D, Wu J, Zhang J. JAK2 inhibitors improve RA combined with pulmonary fibrosis in rats by downregulating SMAD3 phosphorylation. Int J Rheum Dis 2024; 27:e15164. [PMID: 38706209 DOI: 10.1111/1756-185x.15164] [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: 07/17/2023] [Revised: 01/01/2024] [Accepted: 04/14/2024] [Indexed: 05/07/2024]
Abstract
BACKGROUND JAK inhibitors are well known for the treatment of rheumatoid arthritis (RA), but whether they can be used to treat pulmonary fibrosis, a common extra-articular disease of RA, remains to be clarified. METHODS A jak2 inhibitor, CEP33779 (CEP), was administered to a rat model of RA-associated interstitial lung disease to observe the degree of improvement in both joint swelling and pulmonary fibrosis. HFL1 cells were stimulated with TGF-β1 to observe the expression of p-JAK2. Then, different concentrations of related gene inhibitors (JAK2, TGFβ-R1/2, and p-STAT3) or silencers (STAT3, JAK2) were administered to HFL1 cells, and the expression levels of related proteins were detected to explore the underlying mechanisms of action. RESULTS CEP not only reduced the degree of joint swelling and inflammation in rats but also improved lung function, inhibited the pro-inflammatory factors IL-1β and IL-6, reduced lung inflammation and collagen deposition, and alleviated lung fibrosis. CEP decreased the expression levels of TGFβ-R2, p-SMAD, p-STAT3, and ECM proteins in rat lung tissues. TGF-β1 induced HFL1 cells to highly express p-JAK2, with the most pronounced expression at 48 h. The levels of p-STAT3, p-SMAD3, and ECM-related proteins were significantly reduced after inhibition of either JAK2 or STAT3. CONCLUSION JAK2 inhibitors may be an important and novel immunotherapeutic drug that can improve RA symptoms while also delaying or blocking the development of associated pulmonary fibrotic disease. The mechanism may be related to the downregulation of p-STAT3 protein via inhibition of the JAK2/STAT signaling pathway, which affects the phosphorylation of SMAD3.
Collapse
Affiliation(s)
- Yimei Wei
- Department of Geriatrics, Chongqing Medical University, Chongqing, China
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| | - Dandan Wang
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
- Department of Pulmonary Department of Respiratory and Critical Care Medicine, Southwest Medical University, Luzhou, China
| | - Juan Wu
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| | - Jie Zhang
- Department Geriatrics, Chongqing General Hospital, Chongqing, China
| |
Collapse
|
|
9
|
Song L, Zhang W, Tang SY, Luo SM, Xiong PY, Liu JY, Hu HC, Chen YQ, Jia B, Yan QH, Tang SQ, Huang W. Natural products in traditional Chinese medicine: molecular mechanisms and therapeutic targets of renal fibrosis and state-of-the-art drug delivery systems. Biomed Pharmacother 2024; 170:116039. [PMID: 38157643 DOI: 10.1016/j.biopha.2023.116039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/04/2023] [Accepted: 12/14/2023] [Indexed: 01/03/2024] Open
Abstract
Renal fibrosis (RF) is the end stage of several chronic kidney diseases. Its series of changes include excessive accumulation of extracellular matrix, epithelial-mesenchymal transition (EMT) of renal tubular cells, fibroblast activation, immune cell infiltration, and renal cell apoptosis. RF can eventually lead to renal dysfunction or even renal failure. A large body of evidence suggests that natural products in traditional Chinese medicine (TCM) have great potential for treating RF. In this article, we first describe the recent advances in RF treatment by several natural products and clarify their mechanisms of action. They can ameliorate the RF disease phenotype, which includes apoptosis, endoplasmic reticulum stress, and EMT, by affecting relevant signaling pathways and molecular targets, thereby delaying or reversing fibrosis. We also present the roles of nanodrug delivery systems, which have been explored to address the drawback of low oral bioavailability of natural products. This may provide new ideas for using natural products for RF treatment. Finally, we provide new insights into the clinical prospects of herbal natural products.
Collapse
Affiliation(s)
- Li Song
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wei Zhang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shi-Yun Tang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610032, China
| | - Si-Min Luo
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou 571199, China
| | - Pei-Yu Xiong
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Jun-Yu Liu
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Heng-Chang Hu
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Ying-Qi Chen
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou 571199, China
| | - Bo Jia
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qian-Hua Yan
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, China.
| | - Song-Qi Tang
- College of Traditional Chinese Medicine, Hainan Medical University, Haikou 571199, China.
| | - Wei Huang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| |
Collapse
|
|
10
|
Sinha SK, Nicholas SB. Pathomechanisms of Diabetic Kidney Disease. J Clin Med 2023; 12:7349. [PMID: 38068400 PMCID: PMC10707303 DOI: 10.3390/jcm12237349] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/15/2023] [Accepted: 11/22/2023] [Indexed: 03/15/2024] Open
Abstract
The worldwide occurrence of diabetic kidney disease (DKD) is swiftly rising, primarily attributed to the growing population of individuals affected by type 2 diabetes. This surge has been transformed into a substantial global concern, placing additional strain on healthcare systems already grappling with significant demands. The pathogenesis of DKD is intricate, originating with hyperglycemia, which triggers various mechanisms and pathways: metabolic, hemodynamic, inflammatory, and fibrotic which ultimately lead to renal damage. Within each pathway, several mediators contribute to the development of renal structural and functional changes. Some of these mediators, such as inflammatory cytokines, reactive oxygen species, and transforming growth factor β are shared among the different pathways, leading to significant overlap and interaction between them. While current treatment options for DKD have shown advancement over previous strategies, their effectiveness remains somewhat constrained as patients still experience residual risk of disease progression. Therefore, a comprehensive grasp of the molecular mechanisms underlying the onset and progression of DKD is imperative for the continued creation of novel and groundbreaking therapies for this condition. In this review, we discuss the current achievements in fundamental research, with a particular emphasis on individual factors and recent developments in DKD treatment.
Collapse
Affiliation(s)
- Satyesh K. Sinha
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
- College of Medicine, Charles R Drew University of Medicine and Science, Los Angeles, CA 90059, USA
| | - Susanne B. Nicholas
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA;
| |
Collapse
|
|
11
|
Liu Y, Wang W, Zhang J, Gao S, Xu T, Yin Y. JAK/STAT signaling in diabetic kidney disease. Front Cell Dev Biol 2023; 11:1233259. [PMID: 37635867 PMCID: PMC10450957 DOI: 10.3389/fcell.2023.1233259] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 07/28/2023] [Indexed: 08/29/2023] Open
Abstract
Diabetic kidney disease (DKD) is the most important microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD) worldwide. The Janus kinase/signal transducer and activator of the transcription (JAK/STAT) signaling pathway, which is out of balance in the context of DKD, acts through a range of metabolism-related cytokines and hormones. JAK/STAT is the primary signaling node in the progression of DKD. The latest research on JAK/STAT signaling helps determine the role of this pathway in the factors associated with DKD progression. These factors include the renin-angiotensin system (RAS), fibrosis, immunity, inflammation, aging, autophagy, and EMT. This review epitomizes the progress in understanding the complicated explanation of the etiologies of DKD and the role of the JAK/STAT pathway in the progression of DKD and discusses whether it can be a potential target for treating DKD. It further summarizes the JAK/STAT inhibitors, natural products, and other drugs that are promising for treating DKD and discusses how these inhibitors can alleviate DKD to explore possible potential drugs that will contribute to formulating effective treatment strategies for DKD in the near future.
Collapse
Affiliation(s)
- Yingjun Liu
- Clinical Medicine Department, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenkuan Wang
- Clinical Medicine Department, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jintao Zhang
- Clinical Medicine Department, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shuo Gao
- Clinical Medicine Department, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tingting Xu
- Clinical Medicine Department, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yonghui Yin
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| |
Collapse
|
|
12
|
Ren Y, Yu M, Zheng D, He W, Jin J. Lysozyme promotes renal fibrosis through the JAK/STAT3 signal pathway in diabetic nephropathy. Arch Med Sci 2023; 20:233-247. [PMID: 38414445 PMCID: PMC10895955 DOI: 10.5114/aoms/170160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 07/29/2023] [Indexed: 02/29/2024] Open
Abstract
Introduction Diabetic nephropathy (DN) is a leading cause of kidney failure. Lysozyme (LYZ) is an essential component of innate immunity and exhibits antibacterial properties. However, LYZ has been reported to induce nephropathy, implying a possible association between impaired renal function and lysozyme expression. Material and methods Bioinformatics analysis was used to predict the hub gene associated with DN, and the differential expression of the hub gene was confirmed using a mouse model. A mouse model of streptozotocin (STZ)-induced diabetic nephropathy was established to investigate the correlation between DN and LYZ expression, and the functionality of LYZ was verified through knockdown and overexpression experiments conducted in vivo. Immunohistochemistry (IHC) was utilized to assess fibrosis-related markers and cytokines, while Masson staining was performed to assess renal fibrosis. Fibroblast proliferation was assessed using the Cell Counting Kit-8 (CCK-8) assay. The role of the JAK pathway was confirmed using the JAK inhibitor AG490, and Western blot was used to investigate the underlying mechanisms. Results Mechanistically, 25 mM glucose promotes the expression of LYZ in fibroblastic cells, and LYZ may in turn promote the proliferation of renal interstitial fibroblasts. Western blot shows that glucose can activate STAT3 in an LYZ-dependent manner, and the JAK inhibitor AG490 can partially suppress LYZ-induced STAT3 activation. Furthermore, in vivo observations have revealed that overexpression of LYZ is associated with the senescent phenotype of renal tubular epithelial cells (RTECs). Conclusions Lysozyme promotes kidney fibrosis via the JAK/STAT3 signaling pathway in diabetic nephropathy, and glucose may promote fibroblast proliferation by promoting LYZ auto-secretion.
Collapse
Affiliation(s)
- Yan Ren
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Mengjie Yu
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Danna Zheng
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Wenfang He
- Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Juan Jin
- Department of Nephrology, The First People's Hospital of Hangzhou Lin'an District, Affiliated Lin'an People's Hospital, Hangzhou Medical College, Hangzhou, China
| |
Collapse
|
|
13
|
Xue C, Yao Q, Gu X, Shi Q, Yuan X, Chu Q, Bao Z, Lu J, Li L. Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer. Signal Transduct Target Ther 2023; 8:204. [PMID: 37208335 DOI: 10.1038/s41392-023-01468-7] [Citation(s) in RCA: 208] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 04/22/2023] [Indexed: 05/21/2023] Open
Abstract
The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT-related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.
Collapse
Affiliation(s)
- Chen Xue
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qinfan Yao
- Kidney Disease Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinyu Gu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qingmiao Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qingfei Chu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhengyi Bao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
14
|
Liu J, Wang F, Luo F. The Role of JAK/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms. Biomolecules 2023; 13:biom13010119. [PMID: 36671504 PMCID: PMC9855819 DOI: 10.3390/biom13010119] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/25/2022] [Accepted: 12/27/2022] [Indexed: 01/11/2023] Open
Abstract
There are four members of the JAK family and seven of the STAT family in mammals. The JAK/STAT molecular pathway could be activated by broad hormones, cytokines, growth factors, and more. The JAK/STAT signaling pathway extensively mediates various biological processes such as cell proliferation, differentiation, migration, apoptosis, and immune regulation. JAK/STAT activation is closely related to growth and development, homeostasis, various solid tumors, inflammatory illness, and autoimmune diseases. Recently, with the deepening understanding of the JAK/STAT pathway, the relationship between JAK/STAT and the pathophysiology of fibrotic diseases was noticed, including the liver, renal, heart, bone marrow, and lung. JAK inhibitor has been approved for myelofibrosis, and subsequently, JAK/STAT may serve as a promising target for fibrosis in other organs. Therefore, this article reviews the roles and mechanisms of the JAK/STAT signaling pathway in fibrotic diseases.
Collapse
Affiliation(s)
- Jia Liu
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Faping Wang
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fengming Luo
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
- Correspondence: ; Tel.: +86-18980601355
| |
Collapse
|
|
15
|
Sanaye MM, Kavishwar SA. Diabetic Neuropathy: Review on Molecular Mechanisms. Curr Mol Med 2023; 23:97-110. [PMID: 34397329 DOI: 10.2174/1566524021666210816093111] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 12/16/2022]
Abstract
Diabetic mellitus is a worldwide endocrine and metabolic disorder with insulin insensitivity or deficiency or both whose prevalence could rise up to 592 million by 2035. Consistent hyperglycemia leads to one of the most common comorbidities like Diabetic Peripheral Neuropathy (DPN). DPN is underlined with unpleasant sensory experience, such as tingling and burning sensation, hyperalgesia, numbness, etc. Globally, 50-60% of the diabetic population is suffering from such symptoms as microvascular complications. Consistent hyperglycemia during DM causes activation/inhibition of various pathways playing important role in the homeostasis of neurons and other cells. Disruption of these pathways results into apoptosis and mitochondrial dysfunctions, causing neuropathy. Among these, pathways like Polyol and PARP are some of the most intensively studied ones whereas those like Wnt pathway, Mitogen activated protein kinase (MAPK), mTOR pathway are comparatively newly discovered. Understanding of these pathways and their role in pathophysiology of DN underlines a few molecules of immense therapeutic value. The inhibitors or activators of these molecules can be of therapeutic importance in the management of DPN. This review, hence, focuses on these underlying molecular mechanisms intending to provide therapeutically effective molecular targets for the treatment of DPN.
Collapse
Affiliation(s)
- Mrinal M Sanaye
- Department of Pharmacology, Prin. K.M. Kundnani College of Pharmacy, Mumbai-400005, India
| | - Samruddhi A Kavishwar
- Department of Pharmacology, Prin. K.M. Kundnani College of Pharmacy, Mumbai-400005, India
| |
Collapse
|
|
16
|
Liu J, Zhang Y, Liu M, Shi F, Cheng B. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway. Open Med (Wars) 2023; 18:20230683. [PMID: 37034500 PMCID: PMC10080708 DOI: 10.1515/med-2023-0683] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 02/22/2023] [Accepted: 03/02/2023] [Indexed: 04/11/2023] Open
Abstract
Insulin-like-growth factor-1 (IGF-1) is the ligand for insulin-like growth factor-1 receptor (IGF-1R), and the roles of IGF-1/IGF-1R in diabetic nephropathy (DN) are well-characterized previously. However, the biological functions of AG1024 (an IGF-1R inhibitor) in DN remain unknown. This study investigates the roles and related mechanisms of AG-1024 in DN. The experimental DN was established via intraperitoneal injection of streptozotocin, and STZ-induced diabetic rats were treated with AG1024 (20 mg/kg/day) for 8 weeks. The 24 h proteinuria, blood glucose level, serum creatinine, and blood urea nitrogen were measured for biochemical analyses. The increase in 24 h proteinuria, blood glucose level, serum creatinine, and blood urea of DN rats were conspicuously abated by AG1024. After biochemical analyses, the renal tissue specimens were collected, and as revealed by hematoxylin and eosin staining and Masson staining, AG-1024 mitigated typical renal damage and interstitial fibrosis in DN rats. Then, the anti-inflammatory effect of AG-1024 was assessed by western blotting and ELISA. Mechanistically, AG-1024 upregulated SOCS1 and SOCS3 expression and decreased phosphorylated JAK2, STAT1, and STAT3, as shown by western blotting. Collectively, AG-1024 (an IGF-1R inhibitor) ameliorates renal injury in experimental DN by attenuating renal inflammation and fibrosis via the SOCS/JAK2/STAT pathway.
Collapse
Affiliation(s)
- Jianhua Liu
- Department of Nephrology, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Wuhan 430015, Hubei, China
| | - Yun Zhang
- Department of Nephrology, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Wuhan 430015, Hubei, China
| | - Min Liu
- Department of Nephrology, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Wuhan 430015, Hubei, China
| | - Feng Shi
- Department of Nephrology, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Wuhan 430015, Hubei, China
| | - Bo Cheng
- Department of Nephrology, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), No. 168, Hong Kong Road, Jiang’an District, Wuhan 430015, Hubei, China
| |
Collapse
|
|
17
|
Xu S, Yang X, Chen Q, Liu Z, Chen Y, Yao X, Xiao A, Tian J, Xie L, Zhou M, Hu Z, Zhu F, Xu X, Hou F, Nie J. Leukemia inhibitory factor is a therapeutic target for renal interstitial fibrosis. EBioMedicine 2022; 86:104312. [PMID: 36335669 PMCID: PMC9646860 DOI: 10.1016/j.ebiom.2022.104312] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 09/28/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND The role of the IL6 family members in organ fibrosis, including renal interstitial fibrosis (TIF), has been widely explored. However, few studies have ever simultaneously examined them in the same cohort of patients. Besides, the role of leukemia inhibitory factor (LIF) in TIF remains unclear. METHODS RNA-seq data of kidney biopsies from chronic kidney disease (CKD) patients, in both public databases and our assays, were used to analyze transcript levels of IL6 family members. Two TIF mouse models, the unilateral ureteral obstruction (UUO) and the ischemia reperfusion injury (IRI), were employed to validate the finding. To assess the role of LIF in vivo, short hairpin RNA, lenti-GFP-LIF was used to knockdown LIF receptor (LIFR), overexpress LIF, respectively. LIF-neutralizing antibody was used in therapeutic studies. Whether urinary LIF could be used as a promising predictor for CKD progression was investigated in a prospective observation patient cohort. FINDINGS Among IL6 family members, LIF is the most upregulated one in both human and mouse renal fibrotic lesions. The mRNA level of LIF negatively correlated with eGFR with the strongest correlation and the smallest P value. Baseline urinary concentrations of LIF in CKD patients predict the risk of CKD progression to end-stage kidney disease by Kaplan-Meier analysis. In mouse TIF models, knockdown of LIFR alleviated TIF; conversely, overexpressing LIF exacerbated TIF. Most encouragingly, visible efficacy against TIF was observed by administering LIF-neutralizing antibodies to mice. Mechanistically, LIF-LIFR-EGR1 axis and Sonic Hedgehog signaling formed a vicious cycle between fibroblasts and proximal tubular cells to augment LIF expression and promote the pro-fibrotic response via ERK and STAT3 activation. INTERPRETATION This study discovered that LIF is a noninvasive biomarker for the progression of CKD and a potential therapeutic target of TIF. FUNDINGS Stated in the Acknowledgements section of the manuscript.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Fanfan Hou
- Corresponding author. Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Jing Nie
- Corresponding author. Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
18
|
Kim YA, Gu H, Gwon MG, An HJ, Bae S, Leem J, Jung HJ, Park KK, Lee SJ. Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model. Int J Mol Sci 2022; 23:11365. [PMID: 36232665 PMCID: PMC9569483 DOI: 10.3390/ijms231911365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/23/2022] [Accepted: 09/24/2022] [Indexed: 11/16/2022] Open
Abstract
The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring-type non-coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)-induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory-related markers (interleukin-1β, tumor necrosis factor-α), and that of fibrosis (α-smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy-related markers, microtubule-associated protein light chain 3, Beclin1, and autophagy-related gene 5-12. We confirmed that ring-type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury.
Collapse
Affiliation(s)
- Young-Ah Kim
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Hyemin Gu
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Mi-Gyeong Gwon
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Hyun-Jin An
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Seongjae Bae
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Hyun Jin Jung
- Department of Urology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Kwan-Kyu Park
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| | - Sun-Jae Lee
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea
| |
Collapse
|
|
19
|
Cao H, Rao X, Jia J, Yan T, Li D. Exploring the pathogenesis of diabetic kidney disease by microarray data analysis. Front Pharmacol 2022; 13:932205. [PMID: 36059966 PMCID: PMC9428563 DOI: 10.3389/fphar.2022.932205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/07/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic kidney disease (DKD) is a major complication of diabetes mellitus, and the leading contributor of end-stage renal disease. Hence, insights into the molecular pathogenesis of DKD are urgently needed. The purpose of this article is to reveal the molecular mechanisms underlying the pathogenesis of DKD. The microarray datasets of GSE30528 and GSE30529 were downloaded from the NCBI Gene Expression Omnibus (GEO) database to identify the common differentially expressed genes (DEGs) between the glomerular DKD (GDKD) and tubular DKD (TDKD), respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to analyze the function and pathways of the common DEGs. After constructing the protein–protein interaction (PPI) network and subnetwork analysis, three types of analyses were performed, namely, identification of hub genes, analysis of the coexpressed network, and exploration of transcription factors (TFs). Totally, 348 and 463 DEGs were identified in GDKD and TDKD, respectively. Then, 66 common DEGs (63 upregulated DEGs and three downregulated DEGs) were obtained in DKD patients. GO and KEGG pathway analyses revealed the importance of inflammation response, immune-related pathways, and extracellular matrix-related pathways, especially chemokines and cytokines, in DKD. Fifteen hub genes from the 66 common DEGs, namely, IL10RA, IRF8, LY86, C1QA, C1QB, CD53, CD1C, CTSS, CCR2, CD163, CCL5, CD48, RNASE6, CD52, and CD2 were identified. In summary, through the microarray data analysis, the common functions and hub genes greatly contribute to the elucidation of the molecular pathogenesis associated with DKD.
Collapse
Affiliation(s)
- Haiyan Cao
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiaosheng Rao
- Department of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Junya Jia
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tiekun Yan
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
| | - Dong Li
- Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, China
- *Correspondence: Dong Li,
| |
Collapse
|
|
20
|
Zhao J, Guo S, Schrodi SJ, He D. Trends in the Contribution of Genetic Susceptibility Loci to Hyperuricemia and Gout and Associated Novel Mechanisms. Front Cell Dev Biol 2022; 10:937855. [PMID: 35813212 PMCID: PMC9259951 DOI: 10.3389/fcell.2022.937855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 05/31/2022] [Indexed: 11/14/2022] Open
Abstract
Hyperuricemia and gout are complex diseases mediated by genetic, epigenetic, and environmental exposure interactions. The incidence and medical burden of gout, an inflammatory arthritis caused by hyperuricemia, increase every year, significantly increasing the disease burden. Genetic factors play an essential role in the development of hyperuricemia and gout. Currently, the search on disease-associated genetic variants through large-scale genome-wide scans has primarily improved our understanding of this disease. However, most genome-wide association studies (GWASs) still focus on the basic level, whereas the biological mechanisms underlying the association between genetic variants and the disease are still far from well understood. Therefore, we summarized the latest hyperuricemia- and gout-associated genetic loci identified in the Global Biobank Meta-analysis Initiative (GBMI) and elucidated the comprehensive potential molecular mechanisms underlying the effects of these gene variants in hyperuricemia and gout based on genetic perspectives, in terms of mechanisms affecting uric acid excretion and reabsorption, lipid metabolism, glucose metabolism, and nod-like receptor pyrin domain 3 (NLRP3) inflammasome and inflammatory pathways. Finally, we summarized the potential effect of genetic variants on disease prognosis and drug efficacy. In conclusion, we expect that this summary will increase our understanding of the pathogenesis of hyperuricemia and gout, provide a theoretical basis for the innovative development of new clinical treatment options, and enhance the capabilities of precision medicine for hyperuricemia and gout treatment.
Collapse
Affiliation(s)
- Jianan Zhao
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Shicheng Guo
- Computation and Informatics in Biology and Medicine, University of WI-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of WI-Madison, Madison, WI, United States
| | - Steven J. Schrodi
- Computation and Informatics in Biology and Medicine, University of WI-Madison, Madison, WI, United States
- Department of Medical Genetics, School of Medicine and Public Health, University of WI-Madison, Madison, WI, United States
| | - Dongyi He
- Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Guanghua Clinical Medical College, Shanghai University of Traditional Chinese Medicine, Shanghai, Shanghai, China
- Arthritis Institute of Integrated Traditional and Western Medicine, Shanghai Chinese Medicine Research Institute, Shanghai, China
- Institute of Arthritis Research in Integrative Medicine, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
21
|
Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy. Acta Pharmacol Sin 2022; 43:659-671. [PMID: 34103688 PMCID: PMC8888565 DOI: 10.1038/s41401-021-00689-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 04/26/2021] [Indexed: 02/05/2023]
Abstract
Tubulointerstitial inflammation plays an important role in the progression of diabetic nephropathy (DN), and tubular epithelial cells (TECs) are crucial promoters of the inflammatory cascade. Exchange protein activated by cAMP (Epac) has been shown to suppress the angiotensin II (Ang-II)-induced release of inflammatory cytokines in tubular cells. However, the role of Epac in TEC-mediated tubulointerstitial inflammation in DN remains unknown. We found that administering the Epac agonist 8-pCPT-2'-O-Me-cAMP (8-O-cAMP) to db/db mice inhibited tubulointerstitial inflammation characterized by macrophage infiltration and increased inflammatory cytokine release and consequently alleviated tubulointerstitial fibrosis in the kidney. Furthermore, 8-O-cAMP administration restored CCAAT/enhancer binding protein β (C/EBP-β) expression and further upregulated the expression of Suppressor of cytokine signaling 3 (SOCS3), while inhibiting p-STAT3, MCP-1, IL-6, and TNF-α expression in the kidney cortex in db/db mice. And in vitro study showed that macrophage migration and MCP-1 expression induced by high glucose (HG, 30 mM) were notably reduced by 8-O-cAMP in human renal proximal tubule epithelial (HK-2) cells. In addition, 8-O-cAMP treatment restored C/EBP-β expression in HK-2 cells and promoted C/EBP-β translocation to the nucleus, where it transcriptionally upregulated SOCS3 expression, subsequently inhibiting STAT3 phosphorylation. Under HG conditions, siRNA-mediated knockdown of C/EBP-β or SOCS3 in HK-2 cells partially blocked the inhibitory effect of Epac activation on the release of MCP-1. In contrast, SOCS3 overexpression inhibited HG-induced activation of STAT3 and MCP-1 expression in HK-2 cells. These findings indicate that Epac activation via 8-O-cAMP ameliorates tubulointerstitial inflammation in DN through the C/EBP-β/SOCS3/STAT3 pathway.
Collapse
|
|
22
|
Adu-Amankwaah J, Adzika GK, Adekunle AO, Ndzie Noah ML, Mprah R, Bushi A, Akhter N, Huang F, Xu Y, Adzraku SY, Nadeem I, Sun H. ADAM17, A Key Player of Cardiac Inflammation and Fibrosis in Heart Failure Development During Chronic Catecholamine Stress. Front Cell Dev Biol 2021; 9:732952. [PMID: 34966735 PMCID: PMC8710811 DOI: 10.3389/fcell.2021.732952] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 11/16/2021] [Indexed: 12/24/2022] Open
Abstract
Heart failure development is characterized by persistent inflammation and progressive fibrosis owing to chronic catecholamine stress. In a chronic stress state, elevated catecholamines result in the overstimulation of beta-adrenergic receptors (βARs), specifically β2-AR coupling with Gαi protein. Gαi signaling increases the activation of receptor-stimulated p38 mitogen-activated-protein-kinases (p38 MAPKs) and extracellular signal-regulated kinases (ERKs). Phosphorylation by these kinases is a common way to positively regulate the catalytic activity of A Disintegrin and Metalloprotease 17 (ADAM17), a metalloprotease that has grown much attention in recent years and has emerged as a chief regulatory hub in inflammation, fibrosis, and immunity due to its vital proteolytic activity. ADAM17 cleaves and activates proinflammatory cytokines and fibrotic factors that enhance cardiac dysfunction via inflammation and fibrosis. However, there is limited information on the cardiovascular aspect of ADAM17, especially in heart failure. Hence, this concise review provides a comprehensive insight into the structure of ADAM17, how it is activated and regulated during chronic catecholamine stress in heart failure development. This review highlights the inflammatory and fibrotic roles of ADAM17’s substrates; Tumor Necrosis Factor α (TNFα), soluble interleukin-6 receptor (sIL-6R), and amphiregulin (AREG). Finally, how ADAM17-induced chronic inflammation and progressive fibrosis aggravate cardiac dysfunction is discussed.
Collapse
Affiliation(s)
| | | | | | | | - Richard Mprah
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | | | - Nazma Akhter
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Fei Huang
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Yaxin Xu
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| | - Seyram Yao Adzraku
- Key Laboratory of Bone Marrow Stem Cell, Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Iqra Nadeem
- Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, China
| | - Hong Sun
- Department of Physiology, Xuzhou Medical University, Xuzhou, China
| |
Collapse
|
|
23
|
Ji A, Shaukat A, Takei R, Bixley M, Cadzow M, Topless RK, Major TJ, Phipps-Green A, Merriman ME, Hindmarsh JH, Stamp LK, Dalbeth N, Li C, Merriman TR. Aotearoa New Zealand Māori and Pacific Population-amplified Gout Risk Variants: CLNK Is a Separate Risk Gene at the SLC2A9 Locus. J Rheumatol 2021; 48:1736-1744. [PMID: 34210831 DOI: 10.3899/jrheum.201684] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The Māori and Pacific (Polynesian) population of Aotearoa New Zealand has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations. METHODS A list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (minor allele frequency > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2528 individuals of Polynesian ancestry. RESULTS We identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-amplified variants were nominally associated with the risk of gout (rs1635712 [KIAA0319], ORmeta = 1.28, Pmeta = 0.03; rs16869924 [CLNK], ORmeta = 1.37, Pmeta = 0.002; rs2070025 [fibrinogen A alpha chain (FGA)], ORmeta = 1.34, Pmeta = 0.02). The CLNK variant, within the established SLC2A9 gout locus, was genetically independent of the association signal at SLC2A9. CONCLUSION We provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in CLNK have previously been associated with gout in other populations, supporting our evidence for the association of this gene with gout.
Collapse
Affiliation(s)
- Aichang Ji
- A. Ji, PhD, Research Fellow, C. Li, PhD, Professor, Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Amara Shaukat
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Riku Takei
- R. Takei, MSc, Scientist, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA
| | - Matthew Bixley
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Murray Cadzow
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Ruth K Topless
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Tanya J Major
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Amanda Phipps-Green
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Marilyn E Merriman
- A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Jennie Harré Hindmarsh
- J. Harré Hindmarsh, PhD, Research Coordinator, Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti East Coast, New Zealand
| | - Lisa K Stamp
- L.K. Stamp, PhD, Professor, Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Nicola Dalbeth
- N. Dalbeth, MD, Professor, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Changgui Li
- A. Ji, PhD, Research Fellow, C. Li, PhD, Professor, Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tony R Merriman
- T.R. Merriman, BSc, Research Assistant, Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China, Department of Biochemistry, University of Otago, Dunedin, New Zealand, and Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA. A. Ji and A. Shaukat contributed equally to this work.
| |
Collapse
|
|
24
|
Zhang Y, Jin D, Kang X, Zhou R, Sun Y, Lian F, Tong X. Signaling Pathways Involved in Diabetic Renal Fibrosis. Front Cell Dev Biol 2021; 9:696542. [PMID: 34327204 PMCID: PMC8314387 DOI: 10.3389/fcell.2021.696542] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 06/08/2021] [Indexed: 12/19/2022] Open
Abstract
Diabetic kidney disease (DKD), as the most common complication of diabetes mellitus (DM), is the major cause of end-stage renal disease (ESRD). Renal interstitial fibrosis is a crucial metabolic change in the late stage of DKD, which is always considered to be complex and irreversible. In this review, we discuss the pathological mechanisms of diabetic renal fibrosis and discussed some signaling pathways that are closely related to it, such as the TGF-β, MAPK, Wnt/β-catenin, PI3K/Akt, JAK/STAT, and Notch pathways. The cross-talks among these pathways were then discussed to elucidate the complicated cascade behind the tubulointerstitial fibrosis. Finally, we summarized the new drugs with potential therapeutic effects on renal fibrosis and listed related clinical trials. The purpose of this review is to elucidate the mechanisms and related pathways of renal fibrosis in DKD and to provide novel therapeutic intervention insights for clinical research to delay the progression of renal fibrosis.
Collapse
Affiliation(s)
- Yuqing Zhang
- Endocrinology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - De Jin
- Endocrinology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaomin Kang
- Endocrinology Department, Guang'anmen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Rongrong Zhou
- Endocrinology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuting Sun
- Endocrinology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengmei Lian
- Endocrinology Department, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaolin Tong
- Endocrinology Department, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| |
Collapse
|
|
25
|
Lin HCH, Paul CR, Kuo CH, Chang YH, Chen WST, Ho TJ, Day CH, Viswanadha VP, Tsai Y, Huang CY. IGF IIRα-triggered pathological manifestations in the heart aggravate renal inflammation in STZ-induced type-I diabetes rats. Aging (Albany NY) 2021; 13:17536-17547. [PMID: 34233296 PMCID: PMC8312445 DOI: 10.18632/aging.203244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 06/04/2021] [Indexed: 11/25/2022]
Abstract
Pathological manifestations in either heart or kidney impact the function of the other and form the basis for the development of cardiorenal syndrome. However, the mechanism or factors involved in such scenario are not completely elucidated. In our study, to find the correlation between late fetal gene expression in diabetic hearts and their influence on diabetic nephropathy, we created a rat model with cardiac specific overexpression of IGF-IIRα, which is an alternative splicing variant of IGFIIR, expressed in pathological hearts. In this study, transgenic rats over expressing cardiac specific IGF-IIRα and non-transgenic animal models established in SD rats were administered with single dose of streptozotocin (STZ, 55 mg/Kg) to induce Type I diabetes. The correlation between IGF-IIRα and kidney damages were further determined based on their intensity of damage in the kidneys. The results show that cardiac specific overexpression of IGF-IIRα elevates the diabetes associated inflammation and morphological changes in the kidneys. The diabetic transgenic rats showed advancement in the pathological features such a renal tubular damage, collagen accumulation and enhancement in STAT3 associated mechanism of renal fibrosis. The results therefore show that that IGF-IIRα expression in the heart during pathological condition may worsen symptoms of diabetic nephropathy in rats.
Collapse
Affiliation(s)
- Henry Cherng-Han Lin
- Graduate Institute of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Catherine Reena Paul
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei 11153, Taiwan
| | - Yung-Hsien Chang
- Department of Chinese Medicine, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
| | - William Shao-Tsu Chen
- Department of Psychiatry, Tzu Chi General Hospital, Hualien 97004, Taiwan.,School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
| | - Tsung-Jung Ho
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien 97004, Taiwan.,Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan.,School of Post-Baccalaureate Chinese Medicine, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan
| | | | | | - Yuhsin Tsai
- Graduate Institute of Chinese Medicine, China Medical University, Taichung 41354, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97004, Taiwan.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.,Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan.,Department of Biotechnology, Asia University, Taichung 413, Taiwan
| |
Collapse
|
|
26
|
Chen D, Liu Y, Chen J, Lin H, Guo H, Wu Y, Xu Y, Zhou Y, Zhou W, Lu R, Zhou J, Wu J. JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes. Eur J Pharmacol 2021; 902:174121. [PMID: 33901462 DOI: 10.1016/j.ejphar.2021.174121] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/13/2021] [Accepted: 04/20/2021] [Indexed: 12/14/2022]
Abstract
Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes and an important cause of end-stage renal disease. Previous studies have shown that the damage to podocyte autophagy is related to the pathogenesis of DKD, and this damage is closely mediated by the Janus kinase (JAK)/signal transductors and the transcription (STAT) signaling pathway. Here, the underlying molecular mechanism of the JAK/STAT signaling pathway regulating podocyte autophagy was investigated. In the present study, compared to controls, DKD mice showed glomerular hypertrophy, increased kidney weight/weight ratio, and increased urinary protein levels, as well as decreased desmin and synaptopodin expression. Meanwhile, levels of triglyceride, total cholesterol, reduced glutathione, and malondialdehyde were also increased in the serum of DKD mice. Further, a lower number of autophagosomes, reduced expression of MAP1LC3 (LC3) in glomeruli, and increased expression of JAK/STAT pathway-related proteins, namely JAK1, JAK2, STAT1, STAT3, STAT5, and STAT6, were observed in DKD mice. In the in vitro experiments, we observed impaired autophagy, enhanced apoptosis, and activated JAK/STAT pathway in podocytes under high glucose conditions. Studies using ruxolitinib inhibitors have showed that suppression of the JAK/STAT pathway in podocytes subjected to high glucose could increase autophagic flux and autophagy-related protein expression. Taken together, the present study demonstrates that high glucose inhibits autophagy by activating the JAK/STAT pathway in mice and podocytes, thereby preventing the efficient removal of damaged proteins and organelles from the body to prevent apoptosis, and ultimately aggravating the progression of podocyte injury and DKD.
Collapse
Affiliation(s)
- Dandan Chen
- Department of Clinical Pharmacy, The Second Aliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Yaoyu Liu
- Department of Clinical Pharmacy, The Second Aliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Junqi Chen
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Hua Lin
- Department of Clinical Pharmacy, The Second Aliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Huijuan Guo
- Department of Pharmacy, Baoan Women's and Children's Hospital, Jinan University, Shenzhen, Guangdong, PR China
| | - Yifan Wu
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Yuan Xu
- Department of Nephrology, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Yuan Zhou
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Wei Zhou
- Department of Clinical Pharmacy, The Second Aliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Ruirui Lu
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China
| | - Jiuyao Zhou
- Department of Pharmacology, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
| | - Junbiao Wu
- Department of Clinical Pharmacy, The Second Aliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
| |
Collapse
|
|
27
|
Li H, Xu W, Liu X, Wang T, Wang S, Liu J, Jiang H. JAK2 deficiency improves erectile function in diabetic mice through attenuation of oxidative stress, apoptosis, and fibrosis. Andrology 2021; 9:1662-1671. [PMID: 34085398 PMCID: PMC8672361 DOI: 10.1111/andr.13061] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 05/11/2021] [Accepted: 05/31/2021] [Indexed: 12/13/2022]
Abstract
Background Janus kinase 2 (JAK2) is activated in diabetic mellitus (DM) conditions and may enhance oxidative stress, apoptosis and fibrosis in many tissues. Whether JAK2 activation is involved in the occurrence of diabetic erectile dysfunction (ED) is unknown. Objectives We performed this study to investigate the effect of JAK2 deficiency on diabetic ED. Materials and methods Conditional JAK2 gene knockout mice (Cre+/+‐JAK2fl/fl) were used, in which JAK2 gene knockout could be induced by tamoxifen. Mice fell into four groups: control, JAK2 knockout (JAK2−/−), DM, and DM with JAK2−/−. DM was induced by intraperitoneal injection of streptozotocin. Two months later, JAK2 gene knockout was induced with tamoxifen in Cre+/+‐JAK2fl/fl mice. After another 2 months, erectile function was measured by electrical stimulation of the cavernous nerve, and penile tissues were harvested. Ratio of maximal intracavernosal pressure (MIP) to mean arterial blood pressure (MAP), expression and phosphorylation of JAK2, oxidative stress level, NO/Cyclic Guanosine Monophosphate (cGMP) pathway, apoptosis, fibrosis, and transforming growth factor beta 1 (TGF‐β1)/Smad/Collagen IV pathway in corpus cavernosum, were measured. Results JAK2 expression was remarkably decreased after induction with tamoxifen. JAK2 was activated in penile tissues of diabetic mice, and JAK2 deficiency could improve the impaired erectile function caused by DM. However, in mice without DM, JAK2 deficiency had no apparent influence on erectile function. Levels of oxidative stress, apoptosis, fibrosis, and TGF‐β1/Smad/Collagen IV pathway were all elevated by DM, whereas JAK2 deficiency lessened these alterations in diabetic mice. Moreover, JAK2 deficiency improved the expression of the down‐regulated NO/cGMP pathway in diabetic mice. In non‐diabetic mice, no apparent changes were found in aforementioned parameters after JAK2 gene knockout. Discussion and conclusion Our study showed that JAK2 deficiency could improve erectile function in diabetic mice, which might be mediated by reduction in oxidative stress, apoptosis, and fibrosis in corpus cavernosum.
Collapse
Affiliation(s)
- Hao Li
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenchao Xu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaming Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jihong Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongyang Jiang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
28
|
Vitamin D protects glomerular mesangial cells from high glucose-induced injury by repressing JAK/STAT signaling. Int Urol Nephrol 2021; 53:1247-1254. [PMID: 33942213 PMCID: PMC8144147 DOI: 10.1007/s11255-020-02728-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 12/02/2020] [Indexed: 01/28/2023]
Abstract
Aim High glucose (HG) induces the production of transforming growth factor (TGF)-β and reactive oxygen species, which further activates JAK/STAT signaling and promotes the synthesis of matrix proteins, contributes to the pathophysiological processes of diabetic nephropathy. This study aims to investigate the protection role of vitamin D (VD) in the kidney in high glucose condition. Methods Rat glomerular mesangial cells were cultured in high glucose medium, with or without VD or VD receptor (VDR) siRNAs treatment. The levels of TGF-β and fibronectin were detected by qRT-PCR, immunoblotting and enzyme-linked immunosorbent assay (ELISA). The levels of phosphorylated JAK2, STAT1 and STAT3, and JAK/STAT signaling downstream genes were examined by immunoblotting and qRT-PCR. Results In rat glomerular mesangial cells, VD treatment can repress the tyrosine phosphorylation of JAK2, STAT1 and STAT3. VD inhibited TGF-β and fibronectin expression which was rescued by vitamin d receptor (VDR) siRNA and STATs inhibitor perficitinib. The JAK/STAT signaling downstream protein coding genes including SOCS1, SOCS3 and type IV collagen were repressed by VD. Meanwhile, the expression of non-coding RNAs such as miR-181a, miR-181b, was repressed by VD, and the expression of miR-34a and Let-7b was upregulated by VD.
Conclusion Vitamin D (VD) treatment inhibits the function of HG on fibronectin production through regulating JAK/STAT pathway. These results provide direct evidences that VD protects glomerular mesangial cells from high glucose-induced injury through repressing JAK/STAT signaling, which has the potential for clinical DN treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11255-020-02728-z.
Collapse
|
|
29
|
Chen B, Jia Y, Lu D, Sun Z. Acute glucose fluctuation promotes in vitro intestinal epithelial cell apoptosis and inflammation via the NOX4/ROS/JAK/STAT3 signaling pathway. Exp Ther Med 2021; 22:688. [PMID: 33986853 PMCID: PMC8112130 DOI: 10.3892/etm.2021.10120] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
High blood glucose commonly occurs in patients with diabetes mellitus, but little is known of its effects on intestinal epithelial cells, or its associated mechanisms of action therein. In the present study, intestinal epithelial cells were assigned to five groups: i) The normal glucose (NG) group, incubated in 5.0 mmol/l glucose; ii) the constant high glucose (CHG) group, treated with 25.0 mmol/l glucose; iii) the intermittent high glucose (IHG) group, treated with alternating doses of 5.0 and 25.0 mmol/l glucose every 8 h; iv) the mannose group, cultured in 25.0 mmol/l mannose (the osmotic control); and v) the IHG glucose + GKT137831 group, pretreated with 100 nmol/l NADPH oxidase 4 (NOX4) inhibitor, GKT137831, and then exposed to IHG. TNF-α, IL-1 and IL-6 levels were quantified using ELISA kits. Intestinal epithelial cell apoptosis was assessed by flow cytometry and oxidative stress was evaluated by reactive oxygen species (ROS) and malondialdehyde (MDA) detection. The expression levels of proteins associated with apoptosis and involved in the signal transduction of Janus kinase (JAK)/STAT3 pathway were assessed using western blot analysis. The results indicated that NOX4 expression was significantly higher in the CHG group than in the NG group (P<0.01), but lower than in the IHG group (P<0.001). The IHG group exhibited apoptosis and oxidative stress accompanied by the most significant increase in MDA, ROS and inflammatory cytokine levels (P<0.001), which was followed by that of the CHG group. Additionally, the IHG group exhibited reduced Bcl-2, as well as enhanced Bax and cleaved caspase-3 levels compared with the CHG group (P<0.001). Furthermore, the level of phosphorylated (p-)JAK/p-STAT3 was increased to a greater extent in the IHG group than in the CHG group (P<0.001). In conclusion, the findings of the present study indicated that CHG may trigger intestinal epithelial cell apoptosis and inflammation through the NOX4/ROS/JAK/STAT3 pathway, which may be aggravated by acute glucose fluctuation.
Collapse
Affiliation(s)
- Bingyu Chen
- Department of Gastroenterology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, P.R. China.,Department of Gastroenterology, Jiangsu Second Chinese Medicine Hospital, Nanjing, Jiangsu 210017, P.R. China
| | - Yuanyuan Jia
- Department of Medical Oncology, The Second People's Hospital of Huai'an, Huaian, Jiangsu 223001, P.R. China
| | - Dongxue Lu
- Department of Gastroenterology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, P.R. China
| | - Zhiguang Sun
- Department of Gastroenterology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210000, P.R. China
| |
Collapse
|
|
30
|
Nishad R, Mukhi D, Singh AK, Motrapu M, Chintala K, Tammineni P, Pasupulati AK. Growth hormone induces mitotic catastrophe of glomerular podocytes and contributes to proteinuria. Cell Death Dis 2021; 12:342. [PMID: 33795655 PMCID: PMC8016968 DOI: 10.1038/s41419-021-03643-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/15/2021] [Accepted: 03/16/2021] [Indexed: 12/13/2022]
Abstract
Glomerular podocytes are integral members of the glomerular filtration barrier in the kidney and are crucial for glomerular permselectivity. These highly differentiated cells are vulnerable to an array of noxious stimuli that prevail in several glomerular diseases. Elevated circulating growth hormone (GH) levels are associated with podocyte injury and proteinuria in diabetes. However, the precise mechanism(s) by which excess GH elicits podocytopathy remains to be elucidated. Previous studies have shown that podocytes express GH receptor (GHR) and induce Notch signaling when exposed to GH. In the present study, we demonstrated that GH induces TGF-β1 signaling and provokes cell cycle reentry of otherwise quiescent podocytes. Though differentiated podocytes reenter the cell cycle in response to GH and TGF-β1, they cannot accomplish cytokinesis, despite karyokinesis. Owing to this aberrant cell cycle event, GH- or TGF-β1-treated cells remain binucleated and undergo mitotic catastrophe. Importantly, inhibition of JAK2, TGFBR1 (TGF-β receptor 1), or Notch prevented cell cycle reentry of podocytes and protected them from mitotic catastrophe associated with cell death. Inhibition of Notch activation prevents GH-dependent podocyte injury and proteinuria. Similarly, attenuation of GHR expression abated Notch activation in podocytes. Kidney biopsy sections from patients with diabetic nephropathy (DN) show activation of Notch signaling and binucleated podocytes. These data indicate that excess GH induced TGF-β1-dependent Notch1 signaling contributes to the mitotic catastrophe of podocytes. This study highlights the role of aberrant GH signaling in podocytopathy and the potential application of TGF-β1 or Notch inhibitors, as a therapeutic agent for DN.
Collapse
Affiliation(s)
- Rajkishor Nishad
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Dhanunjay Mukhi
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Ashish Kumar Singh
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Manga Motrapu
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Kumaraswami Chintala
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Prasad Tammineni
- Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India
| | - Anil K Pasupulati
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India.
| |
Collapse
|
|
31
|
Kim YA, Kim HJ, Gwon MG, Gu H, An HJ, Bae S, Leem J, Jung HJ, Park KK. Inhibitory Effects of STAT3 Transcription Factor by Synthetic Decoy ODNs on Autophagy in Renal Fibrosis. Biomedicines 2021; 9:331. [PMID: 33806080 PMCID: PMC8064438 DOI: 10.3390/biomedicines9040331] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 01/04/2023] Open
Abstract
Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal fibrosis. We investigated the role of the STAT3 in autophagy and its effect on the prevention of interstitial renal fibrosis. In this study, we use synthesized STAT3 decoy oligonucleotides (ODN), which were injected into the tail veins of unilateral ureteral obstruction (UUO) mice, to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and collagen were decreased by STAT3 decoy ODN. The autophagy markers microtubule-associated protein light chain 3 (LC3) and fibronectin, were identified through immunofluorescent staining, indicating that they were reduced in the group injected with ODN. The expressions of LC3, Beclin1, p62, and autophagy-related 5-12 (Atg5-12) and hypoxia inducible factor-1α (HIF-1α) were inhibited in the ODN injection group. We determined the inhibitory effect of autophagy in chronic kidney disease and confirmed that STAT3 decoy ODN effectively inhibited autophagy by inhibiting the expression of STAT3 transcription factors in the UUO group.
Collapse
Affiliation(s)
- Young-Ah Kim
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| | - Hyun-Ju Kim
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| | - Mi-Gyeong Gwon
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| | - Hyemin Gu
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| | - Hyun-Jin An
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| | - Seongjae Bae
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea;
| | - Hyun Jin Jung
- Department of Urology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea;
| | - Kwan-Kyu Park
- Department of Pathology, School of Medicine, Catholic University of Daegu, Daegu 42472, Korea; (Y.-A.K.); (H.-J.K.); (M.-G.G.); (H.G.); (H.-J.A.); (S.B.)
| |
Collapse
|
|
32
|
RCAN1.4 mediates high glucose-induced matrix production by stimulating mitochondrial fission in mesangial cells. Biosci Rep 2021; 40:221739. [PMID: 31894838 PMCID: PMC6970086 DOI: 10.1042/bsr20192759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 11/30/2019] [Accepted: 12/18/2019] [Indexed: 11/17/2022] Open
Abstract
High glucose (HG)-induced mitochondrial dynamic changes and oxidative damage are closely related to the development and progression of diabetic kidney disease (DKD). Recent studies suggest that regulators of calcineurin 1 (RCAN1) is involved in the regulation of mitochondrial function in different cell types, so we investigate the role of RCAN1 in mitochondrial dynamics under HG ambience in rat glomerular mesangial cells (MCs). MCs subjected to HG exhibited an isoform-specific up-regulation of RCAN1.4 at both mRNA and protein levels. RCAN1.4 overexpression induced translocation of Dynamin related protein 1 (Drp1) to mitochondria, mitochondrial fragmentation and depolarization, accompanied by increased matrix production under normal glucose and HG ambience. In contrast, decreasing the expression of RCAN1.4 by siRNA inhibited HG-induced mitochondrial fragmentation and matrix protein up-regulation. Moreover, both mitochondrial fission inhibitor Mdivi-1 and Drp1 shRNA prevented RCAN1.4-induced fibronectin up-regulation, suggesting that RCAN1.4-induced matrix production is dependent on its modulation of mitochondrial fission. Although HG-induced RCAN1.4 up-regulation was achieved by activating calcineurin, RCAN1.4-mediated mitochondrial fragmentation and matrix production is independent of calcineurin activity. These results provide the first evidence for the HG-induced RCAN1.4 up-regulation involving increased mitochondrial fragmentation, leading to matrix protein up-regulation.
Collapse
|
|
33
|
Liao L, Chen J, Zhang C, Guo Y, Liu W, Liu W, Duan L, Liu Z, Hu J, Lu J. LncRNA NEAT1 Promotes High Glucose-Induced Mesangial Cell Hypertrophy by Targeting miR-222-3p/CDKN1B Axis. Front Mol Biosci 2021; 7:627827. [PMID: 33585566 PMCID: PMC7872960 DOI: 10.3389/fmolb.2020.627827] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/21/2020] [Indexed: 12/13/2022] Open
Abstract
Glomerular hypertrophy is an early morphological alteration in diabetic nephropathy. Cyclin-Dependent Kinases have been shown to be required for high glucose (HG)-induced hypertrophy; however, the upstream regulators of CDKN1B in glomerular hypertrophy remain unclear. Herein we describe a novel pathway in which Long noncoding RNA (lncRNA) NEAT1 regulates the progression of mesangial cell hypertrophy via a competing endogenous RNA (ceRNA) mechanism. Real-time PCR was performed to detect the relative NEAT1 and miR-222-3p expressions and further confirmed the relationship between NEAT1 and miR-222-3p. Cell cycle was evaluated by flow cytometry. The related mechanisms were explored by Western blot, RNA immunoprecipitation and chromatin immunoprecipitation assay. We show that NEAT1 forms double stranded RNA (dsRNA) with miR-222-3p, thus limiting miR-222-3p's binding with CDKN1B. This release of CDKN1B mRNA leads to elevated CDKN1B protein expression, resulting in hypertrophy. In addition, we demonstrated that STAT3 which is activated by HG induces the transcription of NEAT1 by binding to its promoter. Our findings underscore an unexpected role of lncRNAs on gene regulation and introduce a new mode of proliferation regulation in mesangial cells.
Collapse
Affiliation(s)
- Lin Liao
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Chen
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chuanfu Zhang
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Guo
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weiwei Liu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenrui Liu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lianxiang Duan
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ziyang Liu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Hu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jianrao Lu
- Department of Nephrology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
34
|
Bao Y, Liang W, Ye Y, Yi B. PERK-Dependent Activation of the JAK2/STAT3 Pathway Contributes to High Glucose-Induced Extracellular Matrix Deposition in Renal Tubular Epithelial Cells. Int J Endocrinol 2021; 2021:8475868. [PMID: 34335747 PMCID: PMC8315854 DOI: 10.1155/2021/8475868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/05/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Although the deposition of extracellular matrix (ECM) is critical leading to tubular damage in diabetic kidney disease (DKD), the mechanism still remains unclear. The purpose of this study was to demonstrate a role for protein kinase R-like endoplasmic reticulum kinase (PERK) (a protein located in the endoplasmic reticulum membrane) in this pathologic process. METHODS NRK-52E cells were grown in the media containing different concentrations of glucose or thapsigargin for different durations. Cells were subsequently incubated with or without AG490, a selective inhibitor of Janus kinase 2 (JAK2) or GSK2606414 (a selective PERK inhibitor). We evaluated the production of TGF-β1, fibronectin, and collagen I proteins by ELISA. The levels of 78 kD-glucose-regulated protein (GRP78) and PERK, as well as the phosphorylation statues of PERK and JAK2/signal transducer and activator of transcription (STAT3), were determined by western blotting analysis. RESULTS We showed that the increased phosphorylation of JAK2 and STAT3 was accompanied by overexpression of TGF-β1 and ECM deposition in high glucose medium. Disruption of the JAK2/STAT3 pathway with AG490 significantly prevents the high glucose-induced increase in TGF-β1, fibronectin, and collagen I. High glucose induced the overproduction of GRP78 and phosphorylation of PERK, which indicated that endoplasmic reticulum stress (ERS) was triggered in NRK-52E cells cultured under high glucose condition. Inhibition of PERK phosphorylation with GSK2606414, however, blocked the effect of JAK2/STAT3 on the production of TGF-β1 and ECM components in NRK-52E cells. CONCLUSION Our data indicated that the ECM accumulation induced by high glucose arouse via the PERK-dependent JAK2/STAT3-signaling pathway in renal tubular epithelial cells.
Collapse
Affiliation(s)
- Yan Bao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Wei Liang
- Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Yingchun Ye
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Bo Yi
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| |
Collapse
|
|
35
|
Hartman RE, Rao PSS, Churchwell MD, Lewis SJ. Novel therapeutic agents for the treatment of diabetic kidney disease. Expert Opin Investig Drugs 2020; 29:1277-1293. [PMID: 32799584 DOI: 10.1080/13543784.2020.1811231] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Diabetic kidney disease (DKD) involves multifaceted pathophysiology which increases the risk of cardiorenal events and mortality. Conventional therapy is limited to renin-angiotensin aldosterone system inhibition and management of hyperglycemia and hypertension. Recent clinical trials have demonstrated promising nephroprotective effects of antihyperglycemic agents thus modifying guideline treatment recommendations for type 2 diabetic patients with chronic kidney disease. AREAS OF COVERED Relevant studies and clinical trials were searched via PubMed and clinicaltrials.gov through August 2020. Authors offer an update on clinical evidence regarding nephroprotective effects and side effects of sodium-glucose-cotransporter-2 (SGLT2) inhibitors, glucagon-like-peptide-1 (GLP1) agonists and dipeptidylpeptidase-4 (DPP4) inhibitors. They discuss the potential benefits of novel therapy targeting DKD pathogenic processes including inflammation, oxidative stress, fibrosis, and vasoconstriction shown in early phases of clinical trials and offer an opinion on key challenges and directions for future progress. EXPERT OPINION SGLT2 inhibitors are the most promising agents for DKD and improving cardiorenal outcomes. Mineralocorticoid-receptor antagonists and janus kinase inhibitors are also promising investigational therapies that target oxidative stress, nitric oxide synthesis, and inflammation. Novel therapeutic targets and the identification of clinically useful biomarkers may provide future therapies that detect early stages of DKD enabling a slower kidney function decline.
Collapse
Affiliation(s)
| | - P S S Rao
- Department of Pharmaceutical Science, University of Findlay , Findlay, OH, USA
| | | | - Susan J Lewis
- Department of Pharmacy Practice, University of Findlay , Findlay, OH, USA
| |
Collapse
|
|
36
|
Ashrafizadeh M, Rafiei H, Mohammadinejad R, Afshar EG, Farkhondeh T, Samarghandian S. Potential therapeutic effects of curcumin mediated by JAK/STAT signaling pathway: A review. Phytother Res 2020; 34:1745-1760. [PMID: 32157749 DOI: 10.1002/ptr.6642] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 01/11/2020] [Accepted: 01/31/2020] [Indexed: 12/11/2022]
Abstract
Curcumin is a naturally occurring nutraceutical compound with a number of therapeutic and biological activities such as antioxidant, anti-inflammatory, anti-diabetic, antitumor, and cardioprotective. This plant-derived chemical has demonstrated great potential in targeting various signaling pathways to exert its protective effects. Signal transducers and activator of transcription (STAT) is one of the molecular pathways involved in a variety of biological processes such as cell proliferation and cell apoptosis. Accumulating data demonstrates that the STAT pathway is an important target in treatment of a number of disorders, particularly cancer. Curcumin is capable of affecting STAT signaling pathway in induction of its therapeutic impacts. Curcumin is able to enhance the level of anti-inflammatory cytokines and improve inflammatory disorders such as colitis by targeting STAT signaling pathway. Furthermore, studies show that inhibition of JAK/STAT pathway by curcumin is involved in reduced migration and invasion of cancer cells. Curcumin normalizes the expression of JAK/STAT signaling pathway to exert anti-diabetic, renoprotective, and neuroprotective impacts. At the present review, we provide a comprehensive discussion about the effect of curcumin on JAK/STAT signaling pathway to direct further studies in this field.
Collapse
Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hossein Rafiei
- Department of Biology, Faculty of Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Elham G Afshar
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Healthy Ageing Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| |
Collapse
|
|
37
|
Strubl S, Torres JA, Spindt AK, Pellegrini H, Liebau MC, Weimbs T. STAT signaling in polycystic kidney disease. Cell Signal 2020; 72:109639. [PMID: 32325185 PMCID: PMC7269822 DOI: 10.1016/j.cellsig.2020.109639] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/13/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
The most common form of polycystic kidney disease (PKD) in humans is caused by mutations in the PKD1 gene coding for polycystin1 (PC1). Among the many identified or proposed functions of PC1 is its ability to regulate the activity of transcription factors of the STAT family. Most STAT proteins that have been investigated were found to be aberrantly activated in kidneys in PKD, and some have been shown to be drivers of disease progression. In this review, we focus on the role of signal transducer and activator of transcription (STAT) signaling pathways in various renal cell types in healthy kidneys as compared to polycystic kidneys, on the mechanisms of STAT regulation by PC1 and other factors, and on the possibility to target STAT signaling for PKD therapy.
Collapse
Affiliation(s)
- Sebastian Strubl
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA; Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jacob A Torres
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Alison K Spindt
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Hannah Pellegrini
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA
| | - Max C Liebau
- Department of Pediatrics and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thomas Weimbs
- Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California Santa Barbara, Santa Barbara, CA 93106-9625, USA.
| |
Collapse
|
|
38
|
Zheng C, Huang L, Luo W, Yu W, Hu X, Guan X, Cai Y, Zou C, Yin H, Xu Z, Liang G, Wang Y. Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice. Cell Death Dis 2019; 10:848. [PMID: 31699972 PMCID: PMC6838321 DOI: 10.1038/s41419-019-2085-0] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 10/14/2019] [Accepted: 10/23/2019] [Indexed: 12/26/2022]
Abstract
Recent evidences indicate that signal transducer and activator of transcription 3 (STAT3) is one of the crucial signaling pathways in the progression of diabetic nephropathy (DN). Here, we investigated the hypothesis that pharmacological blockade of STAT3 limits the progression of DN. Treatment with selective STAT3 inhibitor, S3I-201 for 16 weeks significantly attenuated kidney injuries in streptozotocin (STZ) induced diabetic mice, associated with downregulated expression of TGF-β1, ACE/AT1, and VEGF in diabetic mouse kidneys. Similar results were confirmed using genetic knockdown of STAT3 in mouse kidneys by injections of AAV2 expressing STAT3 shRNA in diabetic mouse. Further, STAT3 localization in kidney tissue was evaluated using immunofluorescent double-staining analysis, which indicated that STAT3 expression was mainly in the tubular epithelial cells. As expected, in renal tubular epithelial NRK-52E cells, high glucose (HG)-induced overexpression of TGF-β1, ACE/AT1, and VEGF were abrogated by S3I-201 pretreatment, as well as by genetic knockdown of STAT3 using specific siRNA sequence. This study found that renal tubular epithelial cells contributed to STAT3-mediated progression of DN and provided the first evidence that pharmacological inhibition of STAT3 attenuates DN.
Collapse
Affiliation(s)
- Chao Zheng
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.,Department of Endocrinology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Lan Huang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wu Luo
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.,Department of Endocrinology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.,The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325400, China
| | - Weihui Yu
- Department of Endocrinology, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xueting Hu
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xinfu Guan
- The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325400, China
| | - Yan Cai
- The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325400, China
| | - Chunpeng Zou
- Department of Ultrasonography, the Second Affiliated Hospital, Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China
| | - Haimin Yin
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.,Department of Endocrinology, the Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Zheng Xu
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Yi Wang
- Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. .,The Affiliated Cangnan Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325400, China.
| |
Collapse
|
|
39
|
Zhou Z, Zhou X, Dong Y, Li M, Xu Y. Formononetin ameliorates high glucose‑induced endothelial dysfunction by inhibiting the JAK/STAT signaling pathway. Mol Med Rep 2019; 20:2893-2901. [PMID: 31524234 DOI: 10.3892/mmr.2019.10512] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 05/09/2019] [Indexed: 11/06/2022] Open
Abstract
High glucose‑induced endothelial Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is associated with the development and progression of the vascular complications of diabetes. The present study aimed to investigate whether formononetin, a biologically active compound isolated from Astragalus membranaceus (Fisch.) Bge, was able to regulate the JAK/STAT signaling pathway, improving endothelial function. In the present study, formononetin was identified to act as a JAK2 inhibitor, similarly to tyrphostin AG 490 (AG490), by significantly inhibiting the phosphorylation and the mRNA expression levels of JAK2 and STAT in HUVECs exposed to high glucose levels. In addition, formononetin and AG490 improved the viability of HUVECs and inhibited the protein expression levels of caspase‑3. Furthermore, formononetin and AG490 attenuated the inflammatory response in HUVECs by downregulating the protein and mRNA expression levels of interleukin (IL)‑1β and intercellular adhesion molecule 1 (ICAM‑1). Formononetin and AG490 also restored nitric oxide (NO) synthesis in HUVECs. Notably, formononetin was able to reverse the abnormal levels of phosphorylated (p)‑JAK2, p‑STAT3, IL‑1β, ICAM‑1 and NO induced by cotreatment with high glucose and IL‑6, an agonist of the JAK/STAT signaling pathway. Additionally, the present results suggested that formononetin restored phenylephrine‑mediated contraction and acetylcholine‑induced relaxation in aortic tissues of rats fed a high‑glucose diet, in a dose‑dependent manner. Collectively, formononetin could improve endothelial function under glucose stress in vivo and in vitro, suggesting that formononetin may represent a novel potential therapeutic compound to treat diabetic vascular complications.
Collapse
Affiliation(s)
- Zhen Zhou
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Xinjian Zhou
- Department of Endocrinology, Xiangyang First People's Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Youhong Dong
- Department of Oncology, Xiangyang First People's Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Mingyi Li
- Department of Endocrinology, Xiangyang First People's Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
| | - Yancheng Xu
- Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|
|
40
|
Xu J, Chen Y, Xing Y, Ye S. Metformin inhibits high glucose-induced mesangial cell proliferation, inflammation and ECM expression through the SIRT1-FOXO1-autophagy axis. Clin Exp Pharmacol Physiol 2019; 46:813-820. [PMID: 31267567 DOI: 10.1111/1440-1681.13120] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 05/27/2019] [Accepted: 05/31/2019] [Indexed: 12/16/2022]
Abstract
The aim of this study was to investigate the role of metformin in high glucose-induced mesangial cell proliferation, inflammation and extracellular matrix (ECM) accumulation and to elucidate the underlying mechanism of metformin function. An MTT assay was used to examine rat mesangial cell (RMC) proliferation. The levels of TNF-α, IL-6 and TGF-β in RMCs were determined by ELISA. The protein expression of fibronectin, collagen IV and autophagy-related proteins (Beclin-1, LC3-I and LC3-II) in RMCs was detected using western blot. Fluorescence microscopy analysis was carried out to evaluate RMC autophagy. Our results showed that high glucose-induced RMC proliferation, inflammation and ECM expression, but these effects were markedly reduced by metformin. We confirmed that metformin suppressed high glucose-induced RMC proliferation, inflammation and ECM expression via induction of autophagy. Mechanistic investigation demonstrated an axis of SIRT1-FOXO1 in RMC autophagy. Our data indicated that metformin inhibits high glucose-induced mesangial cell proliferation, inflammation and ECM expression through a SIRT1-FOXO1-autophagy axis.
Collapse
Affiliation(s)
- Jiang Xu
- School of Medicine, Shandong University, Jinan, China.,Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yan Chen
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Yan Xing
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| |
Collapse
|
|
41
|
Fadda LM, Alhusaini AM, Ali HM, Hasan IH, Badr AM, Zakaria EA. Cross Talk Between TGF-β and JAK Expressions and Nepherotoxicity Induced by Tetrachloromethane: Role of Phytotherapy. Dose Response 2019; 17:1559325819871755. [PMID: 31516401 PMCID: PMC6719478 DOI: 10.1177/1559325819871755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/21/2019] [Accepted: 08/01/2019] [Indexed: 11/22/2022] Open
Abstract
The aim of the current study is to assess the effectiveness of milk thistle seeds (Mth) in combination with Taraxacum officinale (Tof) and/or Camellia sinensis (Csin) against tetrachloromethane (Tcm) renotoxicity in rats. Tetrachloromethane was injected in a single dose, followed by 1-month treatments with Mth, Tof, and Csin alone or in combination. Serum urea, uric acid, and creatinine levels were significantly increased matched with the control group. Masson trichrome stain revealed increase in the deposition of fibrous tissue in the interstitium between the tubules and the renal corpuscles. Immunohistochemical analysis of kidney tissues revealed that Tcm induced an increase in the immune response of tumor growth factor β (TGF-β) and Janus kinase (JAK) protein expressions and cysteine-aspartic acid protease 3 (caspase 3), while B-cell lymphoma 2 (Bcl2) was downregulated. Treatment with the antioxidants in question either alone or in combination ameliorated all kidney function parameters and showed mild immune reactivity toward TGF-β and JAK protein expressions in blood vessels and glomeruli in the kidney tissues and downregulated caspase 3 and activated Bcl2 protein expression. The combination regimen of the 3 antioxidants showed the most significant renoprotective effect. This was also confirmed histopathologically. It was concluded that the antioxidant mixture is considered as a promising candidate toward renal dysfunction and immune reactivity induced by Tcm and other toxicants.
Collapse
Affiliation(s)
- Laila M. Fadda
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Ahlam M. Alhusaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Hanaa M. Ali
- Common First Year, King Saud University, Riyadh, Saudi Arabia
- Department of Genetics and Cytology, National Research Centre, Dokki, Egypt
| | - Iman H. Hasan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Amira M. Badr
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Pharmacology and Toxicology, College of Pharmacy, AIN Shams University, Cairo, Egypt
| | - Enas A. Zakaria
- Pharmaceutics Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
42
|
Eid RA, Alkhateeb MA, El-Kott AF, Eleawa SM, Zaki MSA, Alaboodi SA, Salem Al-Shudiefat AAR, Aldera H, Alnamar NM, Alassiri M, Khalil MA. A high-fat diet rich in corn oil induces cardiac fibrosis in rats by activating JAK2/STAT3 and subsequent activation of ANG II/TGF-1β/Smad3 pathway: The role of ROS and IL-6 trans-signaling. J Food Biochem 2019; 43:e12952. [PMID: 31368573 DOI: 10.1111/jfbc.12952] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 12/20/2022]
Abstract
This study compared the effect of low-fat diet (LFD) and high-fat diet rich in corn oil (HFD-CO) on left ventricular (LV) fibrosis in rats and examined their effect of angiotensin II (ANG II), JAK/STAT, and TGF-1β/smad3 pathways. As compared to LFD which didn't affect any of the measured parameters, HFD-CO-induced type 2 diabetes phenotype and increased LV collagen synthesis. Mechanistically, it increased LV levels of ROS, ANG II, ACE, IL-6, s-IL-6Rα, TGF-β1, Smad-3, and activities of JAK1/2 and STAT1/3. AG490, a JAK2 inhibitor, partially ameliorated these effect while Losartan, an AT1 inhibitor completely abolished collagen synthesis. However, with both treatments, levels of ANG II, IL-6, and s-IL-6Rα, and activity of JAK1/STAT3 remained high, all of which were normalized by co-administration of NAC or IL-6 neutralizing antibody. In conclusion: HFD-CO enhances LV collage synthesis by activation of JAK1/STAT3/ANG II/TGF-1β/smad3 pathway. PRACTICAL APPLICATIONS: We report that chronic consumption of a high-fat diet rich in corn oil (HFD-CO) induces diabetes mellitus phenotype 2 associated with left ventricular (LV) cardiac fibrosis in rats. The findings of this study show that HFD-CO, and through the increasing generation of ROS and IL-6 levels and shedding, could activate LV JAK1/2-STAT1/3 and renin-angiotensin system (RAS) signaling pathways, thus creating a positive feedback between the two which ultimately leads to activation of TGF-1β/Smad3 fibrotic pathway. Herein, we also report a beneficial effect of the antioxidant, NAC, or IL-6 neutralizing antibody in preventing such adverse effects of such HFD-CO. However, this presents a warning message to the current sudden increase in idiopathic cardiac disorders, especially with the big shift in our diets toward n-6 PUFA.
Collapse
Affiliation(s)
- Refaat A Eid
- Department of Clinica Pathology and Anatomy, College of Medicine, King Khalid University (KKU), Abha, Kingdom of Saudi Arabia
| | - Mahmoud A Alkhateeb
- Basic Medical Sciences (Physiology Section), College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Kingdom of Saudi Arabia
| | - Attalla Farag El-Kott
- Department of Biology, College of Science, King Khalid University (KKU), Abha, Kingdom of Saudi Arabia.,Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Samy M Eleawa
- Department of Applied Medical Sciences, College of Health Sciences, PAAET, Safat, Kuwait
| | - Mohamed Samir Ahmed Zaki
- Department of Anatomy, College of Medicine, King Khalid University (KKU), Abha, Kingdom of Saudi Arabia.,Department of Histology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Sultan Abdullah Alaboodi
- Central laboratories, Huraymala General Hospital, Ministry of Health, Riyadh, Kingdom of Saudi Arabia
| | | | - Hussain Aldera
- Basic Medical Sciences (Physiology Section), College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Kingdom of Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia
| | | | - Mohammed Alassiri
- Basic Medical Sciences (Physiology Section), College of Medicine, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Kingdom of Saudi Arabia.,King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia
| | - Mohammad A Khalil
- Department of Basic Medical Sciences, College of Medicine, King Fahid Medical City (KFMC), Riyadh, Kingdom of Saudi Arabia
| |
Collapse
|
|
43
|
Shati AA, El-Kott AF. Acylated ghrelin prevents doxorubicin-induced cardiac intrinsic cell death and fibrosis in rats by restoring IL-6/JAK2/STAT3 signaling pathway and inhibition of STAT1. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:1151-1168. [PMID: 31093684 DOI: 10.1007/s00210-019-01664-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 05/02/2019] [Indexed: 01/12/2023]
Abstract
This study investigated if JAK/STAT signaling pathway mediates doxorubicin (DOX)-induced cell death and fibrosis in left ventricles (LVs) of rats and examined if acylated ghrelin affords protection by modulating this pathway. Male rats (120 ± 5 g) were divided into 6 groups (10 rats each) as follows: control; control + AG (10 ng/kg, s.c.); DOX (an accumulative dose 15 mg/kg, i.p.); DOX + AG, DOX + AG + AG490, a JAK2 inhibitor (5 mg/kg, i.p.); and DOX + AG + [D-Lys3]-GHRP-6; an AG receptor antagonist (3.75 mg/kg, i.p.). All treatments were carried out for 35 days. In rats' LVs, DOX significantly impaired the systolic and diastolic functions, enhanced levels of ROS and MDA, reduced levels of GSH and Bcl-2, and increased mRNA and protein levels of collagen I/III and TGF-β and cleaved caspase-3. In addition, although DOX did not affect JAK1 or JAK2 activity, it significantly increased protein levels of IL-6, decreased STAT3 and p-STAT3 (Tyr701&Ser727), and increased STAT1 and p-STAT1 (Tyr701&Ser727) levels, with a concomitant decrease in ERK1/2 activity and an increase in P38 activity. However, without affecting IL-6 and JAK1/2, AG reversed all of the observed alterations with a significant increase in the levels and activities of JAK2. Similar effects of AG were also seen in control rats. Interestingly, all the beneficial effects afforded by AG were abolished by AG490 and AG + [D-Lys3]-GHRP-6. In conclusion, DOX-induced cardiac toxicity involves stimulation of IL-6, P38, and STAT1 signaling levels whereas the protective effect afforded by AG involves the activation of ERK1/2 and JAK2/STAT3 and inhibition of STAT1.
Collapse
Affiliation(s)
- Ali A Shati
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia.
| | - Attalla Farag El-Kott
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia.,Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
| |
Collapse
|
|
44
|
Pace J, Paladugu P, Das B, He JC, Mallipattu SK. Targeting STAT3 signaling in kidney disease. Am J Physiol Renal Physiol 2019; 316:F1151-F1161. [PMID: 30943069 DOI: 10.1152/ajprenal.00034.2019] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a multifaceted transduction system that regulates cellular responses to incoming signaling ligands. STAT3 is a central member of the JAK/STAT signaling cascade and has long been recognized for its increased transcriptional activity in cancers and autoimmune disorders but has only recently been in the spotlight for its role in the progression of kidney disease. Although genetic knockout and manipulation studies have demonstrated the salutary benefits of inhibiting STAT3 activity in several kidney disease models, pharmacological inhibition has yet to make it to the clinical forefront. In recent years, significant effort has been aimed at suppressing STAT3 activation for treatment of cancers, which has led to the development of a wide variety of STAT3 inhibitors, but only a handful have been tested in kidney disease models. Here, we review the detrimental role of dysregulated STAT3 activation in a variety of kidney diseases and the current progress in the treatment of kidney diseases with pharmacological inhibition of STAT3 activity.
Collapse
Affiliation(s)
- Jesse Pace
- Division of Nephrology, Department of Medicine, Stony Brook University , Stony Brook, New York
| | - Praharshasai Paladugu
- Division of Nephrology, Department of Medicine, Stony Brook University , Stony Brook, New York
| | - Bhaskar Das
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, New York
| | - John C He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, New York
| | - Sandeep K Mallipattu
- Division of Nephrology, Department of Medicine, Stony Brook University , Stony Brook, New York.,Renal Section, Northport Veterans Affairs Medical Center, Northport, New York
| |
Collapse
|
|
45
|
Sun M, Bu W, Li Y, Zhu J, Zhao J, Zhang P, Gu L, Zhang W, Fang Z. Danzhi Jiangtang Capsule ameliorates kidney injury via inhibition of the JAK-STAT signaling pathway and increased antioxidant capacity in STZ-induced diabetic nephropathy rats. Biosci Trends 2018; 12:595-604. [PMID: 30606979 DOI: 10.5582/bst.2018.01255] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Danzhi Jiangtang Capsule (DJC), a traditional Chinese medicinal formula, has been used clinically in treating diabetes and diabetic nephropathy (DN). We previously demonstrated that DJC is capable of improving renal function in patients and rats with DN, but the mechanisms underlying these therapeutic benefits of DJC are not quite clear yet. In this study, STZ-induced diabetic rats were orally administered DJC for 8 weeks. Fasting blood glucose, renal function indicators in the serum, renal index, and the expression of proteins related to JAK-STAT signaling pathway were evaluated at the end of the experiment. The kidneys were sliced for pathological histology. Antioxidant status was assessed by measuring SOD, LPO and MDA in serum. The expression levels of COX2, iNOS, SOCS and the phosphorylation status of JAK2, STAT1, and STAT3 in renal tissues were evaluated by Western blot analyses. IL-6, TNF-α, and MCP-1 expression levels in renal tissues were determined using double-antibody sandwich ELISA. Diabetic renal dysfunction and its associated pathologies were ameliorated by DJC treatment. DJC significantly reversed the high expression of COX2 and iNOS in renal tissues. Furthermore, DJC inhibited the JAK2-STAT1/STAT3-SOCS3 signaling pathway, resulting in decreased concentrations of IL-6, TNF-α, and MCP-1. Moreover, the oxidant status in the kidney was substantially ameliorated by DJC treatment. In conclusion, the ability of DJC to ameliorate diabetic renal dysfunction and the associated pathologies of this disease might be due to its antioxidant capacity and suppression of the JAK2-STAT1/STAT3 cascade.
Collapse
Affiliation(s)
- Min Sun
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Wenjie Bu
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Yan Li
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Jianliang Zhu
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Jindong Zhao
- Department of Endocrinology, the First Affiliated Hospital of Anhui University of TCM
| | - Pingping Zhang
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Lingling Gu
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Wenna Zhang
- Anhui Provincial Key Laboratory of R&D of Chinese Material Medica, School of Life Science, Anhui University
| | - Zhaohui Fang
- Department of Endocrinology, the First Affiliated Hospital of Anhui University of TCM
| |
Collapse
|
|
46
|
Hu TY, Li LM, Pan YZ. CTRP3 inhibits high glucose-induced human glomerular mesangial cell dysfunction. J Cell Biochem 2018; 120:5729-5736. [PMID: 30362596 DOI: 10.1002/jcb.27859] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 09/19/2018] [Indexed: 02/06/2023]
Abstract
C1q/tumour necrosis factor-related protein-3 (CTRP3) is a member of CTRP family, and its blood level is reduced in human and rodent models of obesity and diabetes. However, the role of CTRP3 in diabetic nephropathy remains unclear. This study was designed to examine the effects of CTRP3 on cell proliferation and extracellular matrix (ECM) accumulation in human glomerular mesangial cells (MCs) in response to high glucose (HG), and explore the potential molecular mechanisms. Our results demonstrated that the expression of CTRP3 was significantly decreased by HG stimulation in MCs. In addition, CTRP3 overexpression inhibited MCs proliferation, reactive oxygen species level, and ECM production in HG-stimulated MCs. Mechanistically, CTRP3 overexpression inhibited the activation of the Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway in HG-stimulated MCs. Taken together, these findings indicated that CTRP3 attenuated HG-induced MC proliferation and ECM production through the inactivation of the JAK2/STAT3 signaling pathway. Thus, CTRP3 may be a potential therapeutic target for the treatment of diabetic nephropathy.
Collapse
Affiliation(s)
- Tian-Ying Hu
- Department of Endocrinology, Weinan Central Hospital, Weinan, Shaanxi, China
| | - La-Mei Li
- Department of Infectious Diseases, Weinan Central Hospital, Weinan, Shaanxi, China
| | - Yan-Zi Pan
- Department of Nephropathy, Baoji Traditional Chinese Medicine Hospital, Baoji, Shaanxi, China
| |
Collapse
|
|
47
|
Elsherbiny NM, Zaitone SA, Mohammad HMF, El-Sherbiny M. Renoprotective effect of nifuroxazide in diabetes-induced nephropathy: impact on NFκB, oxidative stress, and apoptosis. Toxicol Mech Methods 2018; 28:467-473. [DOI: 10.1080/15376516.2018.1459995] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Nehal M. Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Sawsan A. Zaitone
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
- Department of Clinical Pharmacology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Hala M. F. Mohammad
- Department of Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mohamed El-Sherbiny
- Anatomy Department, Almaarefa College of Medicine, Riyadh, Saudi Arabia
- Anatomy Department, Mansoura Faculty of Medicine, Mansoura, Egypt
| |
Collapse
|
|
48
|
Astaxanthin Promotes Nrf2/ARE Signaling to Inhibit HG-Induced Renal Fibrosis in GMCs. Mar Drugs 2018; 16:md16040117. [PMID: 29621130 PMCID: PMC5923404 DOI: 10.3390/md16040117] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/30/2018] [Accepted: 03/30/2018] [Indexed: 01/15/2023] Open
Abstract
Oxidative stress is the main cause of diabetic nephropathy (DN) progression. Nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling is a crucial cellular defense system to cope with oxidative stress. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid with remarkable antioxidative capacity. AST exerted renal protective in diabetic rats. This study aimed to determine whether AST could alleviate the pathological progress of DN by activating Nrf2/ARE signaling and diminishing the excessive oxidative stress and fibronectin (FN) accumulation in glomerular mesangial cells (GMCs) challenged with high glucose (HG). In the current study, we found that AST treatment alleviated the metabolic parameters, renal morphology and extracellular matrix (ECM) accumulation in streptozotocin-induced diabetic rats. Additionally, HG induced the adaptively activated Nrf2/ARE signaling and increased the expression of FN, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor-β1 (TGF-β1), as well as the intracellular reactive oxygen species (ROS) generation in GMCs. However, AST treatment strongly promoted the nuclear translocation and transcriptional activity of Nrf2 as well as upregulated the expression of superoxide dismutase (SOD1), NAD(P)H: quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1), ultimately quenching the higher level of ROS and inhibiting the FN, ICAM-1 and TGF-β1 expression induced by HG. Collectively, our data suggest that the renoprotective effect of AST on DN depends on Nrf2/ARE signaling activation, which could be a potentially therapeutic strategy in the treatment of DN.
Collapse
|
|
49
|
Nifuroxazide, a STAT3 inhibitor, mitigates inflammatory burden and protects against diabetes-induced nephropathy in rats. Chem Biol Interact 2018; 281:111-120. [DOI: 10.1016/j.cbi.2017.12.030] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 11/30/2017] [Accepted: 12/26/2017] [Indexed: 01/17/2023]
|
|
50
|
Liu Z, Chen D, Ning F, Du J, Wang H. EGF is highly expressed in hepatocellular carcinoma (HCC) and promotes motility of HCC cells via fibronectin. J Cell Biochem 2018; 119:4170-4183. [DOI: 10.1002/jcb.26625] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 12/18/2017] [Indexed: 12/31/2022]
Affiliation(s)
- Zongcai Liu
- Laboratory Medicine CenterNanfang Hospital, Southern Medical UniversityGuangzhouChina
- The Laboratory of Endocrinology and MetabolismGuangzhou Women and Children's Medical CenterGuangzhou Medical UniversityGuangzhouChina
| | - Danyang Chen
- Guangzhou Institute of PediatricsWomen and Children's Medical CenterGuangzhou Medical UniversityGuangzhouChina
| | - Fen Ning
- Guangzhou Institute of PediatricsWomen and Children's Medical CenterGuangzhou Medical UniversityGuangzhouChina
| | - Jun Du
- Department of Microbial and Biochemical PharmacySchool of Pharmaceutical SciencesSun Yat‐sen UniversityGuangzhouChina
| | - Haifang Wang
- Laboratory Medicine CenterNanfang Hospital, Southern Medical UniversityGuangzhouChina
| |
Collapse
|