The Role of Renal Cell Senescence in Diabetic Kidney Disease: Mechanisms and Therapeutic Advances

Abstract: Diabetic Kidney Disease (DKD), one of the most severe microvascular complications of diabetes, significantly elevates risks of end-stage renal disease and mortality. Despite current therapies, its multifactorial pathogenesis limits effective renoprotection. Cellular senescence, a stable cell cycle arrest state representing an adaptive response to cumulative damage, emerges as a pivotal driver of DKD progression. Hyperglycemic environment directly interferes with cell cycle regulatory mechanisms or indirectly induces cell cycle arrest to accelerate renal cell senescence through various pathways, including mitochondrial dysfunction, impaired autophagy, endoplasmic reticulum stress, oxidative stress, disordered iron metabolism and inflammatory responses. This process ultimately compromises tissue repair mechanisms and exacerbates renal injury. The review systematically synthesizes current knowledge on the core biological hallmarks of cellular senescence and their mechanistic roles across key renal cell types (renal tubular epithelial cells, glomerular endothelial cells, mesangial cells and podocytes) in DKD pathogenesis. Furthermore, we evaluate emerging therapeutic strategies that target cellular senescence-associated pathways, with particular emphasis on the multi-target potential of natural products. By delineating the interplay between metabolic dysregulation and cellular senescence-driven renal decline, this work provides a foundational framework for developing novel interventions to halt DKD progression. Keywords: natural products, cellular senescence, pharmaceutical, diabetic complications, multi-target therapy