Metformin Attenuates Renal Fibrosis in a Mouse Model of Adenine-Induced Renal Injury Through Inhibiting TGF-β1 Signaling Pathways

• Main Authors: Hao Yi, Chunling Huang, Ying Shi, Qinghua Cao, Jason Chen, Xin-Ming Chen, Carol A. Pollock
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-02-01
• Series: Frontiers in Cell and Developmental Biology
• Subjects: metformin; renal fibrosis; adenine-induced renal injury; transforming growth factor β1 signaling pathways; animal model
• Online Access: https://www.frontiersin.org/articles/10.3389/fcell.2021.603802/full

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.