Abstract
It is well-known that all progressive chronic kidney disease (CKD) is pathologically characterized by tubulointerstitial fibrosis process. Multiple studies have shown the critical role of inflammation and fibrosis in the development of CKD. Hence strategies that target inflammatory and fibrotic signaling pathways may provide promising opportunities to protect against renal fibrosis. Metformin has been used as the first-line glucose-lowering agent to treat patients with type 2 diabetes mellitus (T2DM) for over 50 years. Accumulating evidence suggests the potential for additional therapeutic applications of metformin, including mitigation of renal fibrosis. In this study, the anti-fibrotic effects of metformin independent of its glucose-lowering mechanism were examined in an adenine -induced mouse model of CKD. Expressions of inflammatory markers MCP-1, F4/80 and ICAM, fibrotic markers type IV collagen and fibronectin, and the cytokine TGF-β1 were increased in adenine-induced CKD when compared to control groups and significantly attenuated by metformin treatment. Moreover, treatment with metformin inhibited the phosphorylation of Smad3, ERK1/2, and P38 and was associated with activation of the AMP-activated protein kinase (AMPK) in the kidneys of adenine-treated mice. These results indicate that metformin attenuates adenine-induced renal fibrosis through inhibition of TGF-β1 signaling pathways and activation of AMPK, independent of its glucose-lowering action.
Highlights
Chronic kidney disease (CKD) is a global public health problem
urinary albumin and albumin to creatinine ratio (UACR) was significantly increased in adenine exposed group (11.93 ± 0.40 mg/g) compared to control group (6.83 ± 0.05 mg/g) (Figure 1B, p < 0.001), which was reduced by metformin treatment (8.20 ± 0.26 mg/g) (Figure 1B, p < 0.01 vs. adenine treatment)
RT-PCR analyses showed that the mRNA expression of type IV collagen and fibronectin were significantly increased in kidneys of mice administrated adenine compared to the control group, which was attenuated by metformin treatment (Figures 2A,B, p < 0.001)
Summary
All patients with CKD gradually lose kidney function, with the rate of functional decline varying depending on the disease and patient co-morbidity. Current strategies slow the progression of CKD by controlling the underlying cause, including glucose control in Type 1 or type 2 diabetes, treatment of high blood pressure, Metformin in Adenine-Induced Renal Fibrosis specific therapies for glomerulonephritis, interstitial nephritis, polycystic kidney disease, relief of obstruction of the urinary tract and treatment of recurrent kidney infection, etc. When CKD progresses to end-stage kidney failure, dialysis and kidney transplantation are required which usually results in significant associated health and social needs, personal loss of independence, a decline in functional capacity and burdens on the health, and societal support systems. Despite tremendous efforts focused on finding efficient therapies that target the progression of tubulointerstitial fibrosis, few therapies are available
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