Cellular senescence of renal tubular epithelial cells in diabetic kidney disease: emerging mechanisms and targeted interventions.

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease (ESKD), and while current standard treatment strategies can slow disease progression, they are still unable to reverse progressive structural damage to the kidneys. Emerging evidence indicates that the senescence of renal tubular epithelial cells (RTECs) is not only a central feature of early-stage DKD but also a key pathological mechanism driving renal interstitial fibrosis and progressive kidney function decline. This review systematically elucidates the emerging molecular networks governing RTEC senescence within the DKD microenvironment. Specifically, it thoroughly explores the roles of glucolipotoxicity induced by metabolic dysregulation, persistent reactive oxygen species (ROS) stress, DNA damage, senescence-associated secretory phenotype (SASP)-mediated paracrine toxicity, abnormal epigenetic modifications, and failure of endogenous protective mechanisms such as mitophagy. Furthermore, this review provides a brief overview of current potential therapeutic strategies for delaying or eliminating senescent cells, covering research progress and clinical limitations related to sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin, mesenchymal stem cell (MSC) therapy, and potential natural products.