Metformin alleviates renal injury in diabetic rats by inducing Sirt1/FoxO1 autophagic signal axis

Abstract

Diabetic nephropathy (DN) is the major microvascular complication of diabetes mellitus and the most important cause of end‐stage renal disease worldwide. Metformin is the preferred oral hypoglycaemic drug for type 2 diabetes mellitus (T2DM). Recent studies have shown that besides lowering blood glucose, metformin also has protective effects on renal function, but its mechanism is not clear. In this study, we established a diabetic rat model by high‐fat feeding combined with intraperitoneal injection of streptozotocin. Their changes of renal function, oxidative stress, histopathology and structure, and autophagy were observed after 8 weeks of metformin treatment at different dose. Sirt1 inhibitor EX527 and metformin were used to observe whether the protective effect of metformin on DN kidney was achieved through the Sirt1/FoxO1 autophagic signalling pathway. The results showed that metformin could protect renal function by up‐regulating autophagy level, alleviating oxidative stress level of renal tissue and pathological and structural changes of glomeruli, and inhibiting the expression of extracellular matrix. Sirt1 inhibitor could block the protective effect of metformin on kidney of diabetic rats, suggesting that metformin could alleviate kidney injury in diabetic rats by inducing Sirt1/FoxO1 autophagy signal axis. So metformin could alleviate renal injury in diabetic rats, which may be achieved by regulating Sirt1/FoxO1 autophagic signalling pathway and inducing renal autophagy.

P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response

“…Autophagy impairment has been implicated in the pathogenesis of DN [ 1 , 57 ]. Importantly, emerging evidence suggests that targeting the autophagy pathway to activate and restore the autophagy activity is renoprotective against DN [ 8 , 58 , 59 ]. In this regard, we demonstrated that P2Y2R deficiency significantly enhanced autophagy activity, which was altered in DN, by increasing autophagy flux (LC3B-II and p62) and expression of other autophagy-related proteins (ATG5, ATG12, Beclin-1).…”

Accelerated Kidney Aging in Diabetes Mellitus

“…Metformin alleviated inflammation of mesangial cells [ 183 ], which was related to upregulated glucagon-like peptide-1 (GLP-1) receptor expression [ 184 ]. The Sirt1/Foxo1 signal pathway was focused on demonstrating the antioxidative stress effect of metformin subsequently with the activation of autophagy in diabetic rats and high-glucose-induced mesangial cells [ 185 , 186 ]. Increasing PGC-1 α expression in high-glucose-induced TECs and suppression of AKT and mTOR activation in proteinuria induced TECs, subsequently followed by augmented autophagy and mitochondrial dynamics or ER stress that contributed to the renoprotective effects of metformin in DN [ 187 , 188 ].…”

Significance of Metformin Use in Diabetic Kidney Disease

“…Autophagy is a protective mechanism for DKD and is regulated by AMPK and silent mating type information regulation 2 homolog 1 (Sirt1). Sirt1 is a NAD + -dependent deacetylase and increases the expression of FoxO1, a transcription factor that can reduce oxygen-free radicals by inducing autophagy [ 75 , 76 ]. Therefore, the AMPK and Sirt1/FoxO1 axis has been suggested to be a protective signaling pathway in autophagy.…”

“…Therefore, the AMPK and Sirt1/FoxO1 axis has been suggested to be a protective signaling pathway in autophagy. Metformin has been shown to attenuate renal fibrosis and histological changes in the glomerulus via autophagy by activating the AMPK/Sirt1/FoxO1 signaling pathway [ 76 , 77 ].…”