The aim of the study was to compare the role of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluate its mechanism in high-glucose-treated Renal tubular epithelial cells (RTECs) in vitro. Sprague-Dawley (SD) rats were used to establish model of DN, then the changes of biochemical indicators and body weight were measured. The degree of renal fibrosis was quantified via histological analysis, immunohistochemistry, and immunoblot. The

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... underlying relationship between autophagy and DN was analyzed and the cellular regulatory mechanism of metformin on epithelial-to-mesenchymal transition (EMT) was detected. Metformin markedly improved renal function and showed histological restoration of renal tissues especially in the early stage of DN, with a significant improvement of autophagy and a low expression of fibrotic biomarkers (Fibronectin and Collagen I) in renal tissue. RTECs under hyperglycemic conditions exhibited inactivation of p-AMPK and activation of EMT. But the promotion of AMPK activated by metformin significantly improved renal autophagic function, inhibited the EMT of RTECs, attenuated TIF, so as to effectively prevent or delay the course of DN. This evidence provided theoretical and experimental basis for the following research on the potential clinical usefulness of metformin for the treatment of diabetic TIF.