From a Shared Stress to Cell-Type-Specific Responses: The Heterogeneous Mechanisms of High Glucose-Induced Cellular...

Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes characterized by complex pathogenesis in which renal cellular senescence is a critical pathological element. Traditionally, hyperglycemia has been regarded as a uniform stressor inducing cellular senescence; however, significant heterogeneity exists in different renal cell types' responses to high glucose (HG) stimulation. This review systematically elucidates mechanisms underlying senescence of major renal cell types under hyperglycemic conditions. Hyperglycemia acts as a common initiator triggering senescence via shared pathways, including oxidative stress and metabolic dysregulation. However, owing to distinct structural, functional, and molecular profiles across cell types, divergent senescence programs are activated. Specifically, podocyte senescence centers on GSK3β-mediated collapse of metabolic homeostasis and GPR124 axis-related mechanosensing dysfunction; mesangial cell (MC) senescence manifests as STAT5- and Caveolin-1 signaling-mediated "senescence-fibrosis" vicious cycles; glomerular endothelial cell (GEC) senescence is characterized by dysregulation of the NOS/NO signaling axis and glycocalyx damage; and renal tubular epithelial cell (TEC) senescence is initiated by mitochondrial damage under metabolic overload, promoting interstitial fibrosis through the senescence-associated secretory phenotype (SASP). By revealing this heterogeneous mechanism shifting from "common stress" to "specific responses," this review offers a novel perspective on DKD pathogenesis and establishes a theoretical foundation for developing targeted anti-senescence therapies. It further discusses implications for the clinical translation of renal protective agents.