Background: Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease globally, with podocyte injury recognized as a central contributor to proteinuria and disease progression. Caveolin-1 (Cav-1) has been implicated in the regulation of podocyte function, yet its precise role in DKD-related endocytosis and stress responses remains unclear. This study aimed to investigate the role of Cav-1 in podocyte injury, elucidate its molecular mechanisms in regulating endocytosis and stress signaling, and assess the potential contribution of Dynamin-2 in this process.

Methods: Cav-1 knockout mouse models and high-glucose-treated human podocytes (HPCs) were established. Western blotting, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, albumin endocytosis assays, and analyses of protein expression were performed to evaluate the effects of Cav-1 and Dynamin-2 on podocyte endocytic capacity and apoptosis. Expression of endocytosis-related molecules (clathrin heavy chain (CHC), Ras-related protein Rab 5 (Rab5), Rab7, EH-domain containing protein 2 (EHD2), Caveolae-associated protein 1 (CAVIN1)) and signaling pathway proteins (Src family kinases (SFKs), Ras homolog family member A (RhoA)) was also examined.

Results: Under high-glucose conditions, Cav-1 and endocytosis-related proteins (Dynamin-2, CHC, Rab5, Rab7) were significantly upregulated (p < 0.05), accompanied by enhanced podocyte endocytic activity (p < 0.05) and increased apoptosis (p < 0.05). Cav-1 deletion attenuated proteinuria and glomerular pathology in mice (p < 0.05), reduced the proportion of TUNEL-positive cells (p < 0.05), and suppressed the SFKs-RhoA signaling pathway as well as EHD2/CAVIN1 expression (p < 0.05).

Conclusion: Cav-1 serves as a central regulator of DKD-associated podocyte injury, promoting high-glucose-induced damage through cooperative interaction with Dynamin-2. Targeting Cav-1 and Dynamin-2 may provide a novel therapeutic approach to mitigate DKD progression and provide a theoretical basis for translating mechanistic insights into clinical applications.