Early podocyte injury and cellular senescence are critical in the progression of diabetic kidney disease (DKD), often preceding the development of overt albuminuria. Although sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated renoprotective effects, their specific mechanisms in podocytes remain unclear. Therefore, this study aimed to evaluate the impact of dapagliflozin on renal ultrastructure and senescence in the early stages of DKD, using a streptozotocin (STZ)-induced diabetic mouse model fed a high-fat diet (HFD).

Eight-week-old male C57BL/6J mice were induced with early DKD through a combination of a HFD (60% fat) and STZ injection (40 mg/kg/day for 5 days) for 30 weeks. After 6 weeks of HFD feeding, mice were randomized to receive either dapagliflozin (10 mg/kg/day) or vehicle for 24 weeks. Metabolic parameters, insulin sensitivity, urinary markers, and kidney histopathology were assessed. Renal histopathology and cortical tissue analysis were performed after 24 weeks of dapagliflozin treatment.

Dapagliflozin treatment significantly improved random and fasting blood glucose levels, as well as insulin tolerance, compared to the HFD-STZ group. Immunohistochemical analysis showed a 25.02% reduction in glomerular volume and a 30.13% decrease in mesangial expansion in the dapagliflozin-treated group (p = 0.043 and p = 0.0007, respectively) compared to the HFD-STZ group. Transmission electron microscopy revealed marked glomerular basement membrane thickening and podocyte foot process effacement in the STZ-HFD group, which were alleviated in the dapagliflozin-treated group. Synaptopodin expression was significantly reduced in the STZ-HFD group, indicating podocyte dedifferentiation, whereas synaptopodin levels were preserved in the dapagliflozin-treated group, suggesting that dapagliflozin attenuates podocyte dedifferentiation.

Dapagliflozin attenuated diabetic kidney disease in the HFD-STZ mouse model by preserving glomerular structural integrity and podocyte morphology, demonstrating renoprotective effects prior to the onset of significant albuminuria or tubular injury. In addition to its glycemic benefits, dapagliflozin provided ultrastructural evidence of protection against podocytopathy. It directly protects podocytes by attenuating senescence and preserving differentiation. These findings highlight novel mechanisms of renoprotection by SGLT2 inhibitors and support early intervention in DKD, even before overt albuminuria develops.