Metformin attenuates renal fibrosis in both AMPKα2-dependent and independent manners

Metformin is a well-known AMP-activated protein kinase (AMPK) activator, and it has been shown to inhibit organ fibrosis. Whether AMPK alpha 2 mediates metformin protection against renal fibrosis remains unknown. Here, we aimed to investigate the role of the AMPK alpha 2 isoform in mediating the inhibitory effect of metformin on renal fibrosis. Unilateral ureteral obstruction (UUO) was used to induce renal fibrosis in wild-type (WT) and AMPK alpha 2 knockout (AMPK alpha 2(-/-)) mice. Metformin treatment was initiated 3 days before UUO and was continued until 7 days after UUO. In WT mice, metformin significantly inhibited UUO-induced renal fibrosis. In AMPK alpha 2(-/-) mice, metformin also tended to inhibit UUO-induced renal fibrosis. Specifically, metformin significantly -reduced UUO-induced transforming growth factor beta 1 (TGF beta 1) mRNA and protein -expression in WT mice but not in AMPK alpha 2(-/-) mice. In contrast, metformin reduced UUO-induced TGF beta 1 downstream Smad3 phosphorylation in both WT and AMPK alpha 2(-/-) mice, suggesting that this regulation occurs in an AMPK alpha 2-independent manner. In conclusion, the underlying mechanisms for the protective effects of metformin against renal fibrosis include AMPK alpha 2-dependent targeting of TGF beta 1 production and AMPK alpha 2-independent targeting of TGF beta 1 downstream signalling. In this regard, metformin has an advantage over other AMPK activators for the treatment of renal fibrosis.