Metformin alleviates oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway

Abstract

Metformin, as the basic pharmacological therapy and the first preventive drug in type 2 diabetes mellitus (T2DM), is proved to have potential protection in diabetic kidney disease (DKD). Here, we established a diabetic rat model induced by high-fat diet and low dose streptozotocin, and high glucose cultured rat mesangial cells (RMCs) pre-treated with metformin or transfected with AMPK, SIRT1 and FoxO1 small interfering RNA, and detected oxidative stress and autophagy related factors to explore the molecular mechanisms of metformin on DKD via adenosine monophosphate-activated protein kinase (AMPK)/silent mating type information regulation 2 homolog-1 (sirtuin-1, SIRT1)-Forkhead box protein O1 (FoxO1) pathway. We found that metformin effectively alleviated the disorders of glycolipid metabolism, renal function injury in diabetic rats, and relieved oxidative stress, enhanced autophagy and slowed down abnormal cell proliferation in high glucose cultured RMCs through AMPK/SIRT1-FoxO1 pathway, indicating the protective role of metformin against the pathological process of DKD.

Keywords: Autophagy; Diabetic kidney disease; Metformin; Oxidative stress.