Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts

Shen, Yang; Miao, Naijun; Xu, Jianing; Gan, Xinxin; Xu, Dan; Zhou, Li; Xue, Hong; Zhang, Wei; Lü, Limin

doi:10.3390/ijms17020146

Cited by 50 publications

(37 citation statements)

References 29 publications

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“…The confidence intervals were wide, and this finding should be interpreted cautiously. However, in the context of prior studies, the lack of an impact on ESRD incidence suggests that the experimental reductions in renal fibrosis observed with metformin use may not translate into a reduction in progressive GFR loss in diabetes. However, it is possible that the fibrosis present in some enrolled patients with stage G4 CKD was advanced and resistant to anti‐fibrotic treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental studies suggest that metformin may have anti‐fibrotic effects, with the potential for beneficial effects on kidney and cardiovascular disease independent of the direct effect on glycaemic control. However, until recently, metformin was considered unsafe for use in individuals with moderate or severe CKD because of the potential to induce lactic acidosis .…”

Section: Introductionmentioning

confidence: 99%

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Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease

Charytan

Solomon

Ivanovich

et al. 2019

Diabetes Obesity Metabolism

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Aims Metformin could have benefits on cardiovascular disease and kidney disease progression but is often withheld from individuals with diabetes and chronic kidney disease (CKD) because of a concern that it may increase the risk of lactic acidosis. Materials and methods All‐cause mortality, cardiovascular death, cardiovascular events (death, hospitalization for heart failure, myocardial infarction, stroke or myocardial ischemia), end stage renal disease (ESRD) and the kidney disease composite (ESRD or death) were compared in metformin users and non‐users with diabetes and CKD enrolled in the Trial to Reduce Cardiovascular Events with Aranesp (darbepoeitin‐alfa) Therapy (TREAT) (NCT00093015). Outcomes were compared after propensity matching of users and non‐users and in multivariable proportional hazards models. Results There were 591 individuals who used metformin at baseline and 3447 non‐users. Among propensity‐matched users, the crude incidence rate for mortality, cardiovascular mortality, cardiovascular events and the combined endpoint was lower in metformin users than in non‐users, but ESRD was marginally higher (4.0% vs 3.6%). Metformin use was independently associated with a reduced risk of all‐cause mortality (HR, 0.49; 95% CI, 0.36‐0.69), cardiovascular death (HR, 0.49; 95% CI, 0.32‐0.74), the cardiovascular composite (HR, 0.67, 95% CI, 0.51‐0.88) and the kidney disease composite (HR, 0.77; 95% CI, 0.61‐0.98). Associations with ESRD (HR, 1.01; 95% CI, 0.65‐1.55) were not significant. Results were qualitatively similar in adjusted analyses of the full population. Two cases of lactic acidosis were observed. Conclusions Metformin may be safer for use in CKD than previously considered and may lower the risk of death and cardiovascular events in individuals with stage 3 CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease

Charytan

Solomon

Ivanovich

et al. 2019

Diabetes Obesity Metabolism

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“…Shen et al reported that pretreatment with metformin prevents renal fibrosis by preventing angiotensin II-induced ERK1/2 activation and ECM overproduction in angiotensin II-treated renal fibroblast NRK-49F cells [87]. Fluorofenidone treatment inhibits the progression of renal interstitial fibrosis by suppressing oxidative stress and ERK1/2 signaling pathways in rat proximal tubular epithelial cells [88].…”

Section: Com/cpbmentioning

confidence: 99%

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

Luo

Shi

et al. 2016

Cell Physiol Biochem

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Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis. However, the underlying signaling mechanisms, whereby hypoxia alters cellular behaviors, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are key signal-transducing enzymes activated by a wide range of extracellular stimuli, including hypoxia/ischemia. There are four major family members of MAPKs: the extracellular signal-regulated kinases-1 and -2 (ERK1/2), the c-Jun N-terminal kinases (JNK), p38 MAPKs, and extracellular signal-regulated kinase-5 (ERK5/BMK1). Recent studies, including ours, suggest that these MAPKs are differentially involved in renal responses to hypoxic/ischemic stress. This review will discuss their changes in hypoxic/ischemic pathophysiology with acute kidney injury, chronic kidney diseases and renal carcinoma.

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“…The normal overexpression and pathological accumulation of ECM components, such as fibronectin and collagen I, result in ECM deposition [31], thereby decreasing the glomerular infiltration rate, deteriorating renal function, and eventually leading to renal failure. In our study, we demonstrated that fibronectin and collagen I are significantly decreased by treatment with telocytes at both the protein and gene levels.…”

Section: Discussionmentioning

confidence: 99%

Transplantation of Telocytes Attenuates Unilateral Ureter Obstruction-Induced Renal Fibrosis in Rats

Zheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Previous studies imply that telocytes may have a protective effect on fibrosis in various organs, including the liver, colon, and heart. The effect of telocytes on renal fibrosis remains unknown. Herein, this study was designed to investigate the effect of telocytes on renal fibrosis and the potential mechanisms involved. Methods: In a unilateral ureteral obstruction (UUO)-induced renal fibrosis model, telocytes were injected via the tail vein every other day for 10 days. The degree of renal damage and fibrosis was determined using histological assessment. The expression of collagen I, fibronectin, epithelial-mesenchymal transition markers, and Smad2/3 phosphorylation was examined by western blot analyses. Real-time PCR and enzyme-linked immunosorbent assay were performed in vivo to detect the levels of transforming growth factor (TGF)-β1 and various growth factors. Results: Telocytes attenuated renal fibrosis, as evidenced by reduced interstitial collagen accumulation, decreased expression of fibronectin and collagen I, upregulation of E-cadherin, and downregulation of α-smooth muscle actin. Furthermore, telocytes decreased serum TGF-β1 levels, suppressed Smad2/3 phosphorylation, and increased the expression of hepatocyte growth factor (HGF) in rat kidney tissue following UUO. Blockage of HGF counteracted the protective effect of telocytes on UUO-treated kidneys. Through the detection of HGF mRNA levels in vitro, we found that telocytes had no effect on HGF expression compared with renal fibroblasts. Conclusion: Telocytes attenuated UUO-induced renal fibrosis in rats, likely through enhancing the expression of HGF in an indirect manner.

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Metformin Prevents Renal Fibrosis in Mice with Unilateral Ureteral Obstruction and Inhibits Ang II-Induced ECM Production in Renal Fibroblasts

Cited by 50 publications

References 29 publications

Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease

Metformin use and cardiovascular events in patients with type 2 diabetes and chronic kidney disease

Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

Transplantation of Telocytes Attenuates Unilateral Ureter Obstruction-Induced Renal Fibrosis in Rats

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