Mechanism and application of metformin in kidney diseases: An update

Metformin is an oral antihyperglycemic drug widely used to treat type 2 diabetes mellitus (T2DM), acting via indirect activation of 5? Adenosine monophosphate-activated Protein Kinase (AMPK). Beyond the anti-diabetic effect, accumulative pieces of evidence have revealed that metformin also everts a beneficial effect in diverse kidney diseases. In various acute kidney diseases (AKI) animal models, metformin protects renal tubular cells from inflammation, apoptosis, reactive oxygen stress (ROS), endoplasmic reticulum (ER) stress, epithelialmesenchymal transition (EMT) via AMPK activation. In diabetic kidney disease (DKD), metformin also alleviates podocyte loss, mesangial cells apoptosis, and tubular cells senescence through AMPK-mediated signaling pathways. Besides, metformin inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluids secretion and the mammalian target of rapamycin (mTOR)-involved cyst formation negatively regulated by AMPK in autosomal dominant polycystic kidney disease (APDKD). Furthermore, metformin also contributes to the alleviation of urolithiasis and renal cell carcinoma (RCC). As the common pathway for chronic kidney disease (CKD) progressing towards end-stage renal disease (ESRD), renal fibrosis is ameliorated by metformin, to a great extent dependent on AMPK activation. However, clinical data are not always consistent with preclinical data, some clinical investigations showed the unmeaningful even detrimental effect of metformin on T2DM patients with kidney diseases. Most importantly, metformin-associated lactic acidosis (MALA) is a vital issue restricting the application of metformin. Thus, we conclude the application of metformin in kidney diseases and uncover the underlying molecular mechanisms in this review.

Automated summary

Metformin, an oral antihyperglycemic drug, not only treats type 2 diabetes mellitus but also demonstrates beneficial effects in various kidney diseases by activating AMPK. It protects renal cells from inflammation, apoptosis, and stress, alleviates podocyte loss and fibrosis, and inhibits cyst formation. However, clinical data may not always align with preclinical findings, with some showing minimal or negative effects on T2DM patients with kidney diseases. The issue of metformin-associated lactic acidosis also poses challenges to its application.