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

Summary Metformin is a well‐known AMP ‐activated protein kinase ( AMPK ) activator, and it has been shown to inhibit organ fibrosis. Whether AMPK α2 mediates metformin protection against renal fibrosis remains unknown. Here, we aimed to investigate the role of the AMPK α2 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 α2 knockout ( AMPK α2 −/− ) 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 α2 −/− mice, metformin also tended to inhibit UUO ‐induced renal fibrosis. Specifically, metformin significantly reduced UUO ‐induced transforming growth factor β1 ( TGF β1) mRNA and protein expression in WT mice but not in AMPK α2 −/− mice. In contrast, metformin reduced UUO ‐induced TGF β1 downstream Smad3 phosphorylation in both WT and AMPK α2 −/− mice, suggesting that this regulation occurs in an AMPK α2‐independent manner. In conclusion, the underlying mechanisms for the protective effects of metformin against renal fibrosis include AMPK α2‐dependent targeting of TGF β1 production and AMPK α2‐independent targeting of TGF β1 downstream signalling. In this regard, metformin has an advantage over other AMPK activators for the treatment of renal fibrosis.