Molecular mechanisms and therapeutic strategies of glomerular cell senescence in diabetic kidney disease: from heterogeneity to precision intervention

Diabetic kidney disease (DKD) has emerged as a major cause of end-stage renal disease (ESRD) worldwide, with approximately 30%-40% of diabetic patients progressing to DKD and 25% eventually requiring renal replacement therapy. Glomerular cell senescence, a central pathological driver of disease progression, persists throughout the entire course of DKD and involves activation of the complement system, transcription factor regulation, mitochondrial dysfunction, oxidative stress, and DNA damage response (DDR). Despite shared senescence mechanisms, podocytes, endothelial cells, and mesangial cells exhibit distinct senescent heterogeneity. This manuscript explores the core mechanisms regulating glomerular cell senescence and their impact on renal filtration barrier injury, inflammation, and glomerulosclerosis, with a specific focus on the senescent characteristics and interactions of different types of glomerular cells. It also discusses senescence-related diagnostic biomarkers and epigenetic clocks. Our findings highlight the critical role of cell type-specific senescence in the pathogenesis of DKD and propose potential precision therapeutic strategies targeting cellular senescence, offering promising breakthroughs for preventing or alleviating the progression of DKD.