Metformin attenuates endoplasmic reticulum stress in diabetic kidney disease: mechanistic insights and future perspectives.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes that can lead to end-stage renal failure. Emerging evidence suggests that endoplasmic reticulum (ER) stress plays a crucial role in the pathogenesis of DKD by affecting various renal parenchymal cells, including endothelial cells, podocytes, and mesangial cells. This review comprehensively examines the relationship between ER stress and DKD, focusing on how metformin, a first-line antidiabetic medication, ameliorates ER stress-induced kidney injury. Multiple factors, including reactive oxygen species (ROS), proteinuria, and advanced glycation end products (AGEs), contribute to ER stress in DKD. Metformin's renoprotective effects are primarily mediated through activation of the AMPK signaling pathway, which modulates ER stress response, reduction of oxidative stress and its impact on ER function, and improvement of mitochondrial function. These mechanisms collectively lead to decreased proteinuria, reduced cell apoptosis, and attenuated epithelial-mesenchymal transition in diabetic kidneys. Understanding these molecular mechanisms provides new insights into the therapeutic potential of metformin in DKD treatment. However, further research is needed to elucidate the precise molecular pathways through which metformin regulates ER stress in different renal cell types under diabetic conditions.