Kidney dysfunction induced by a hyperpalatable diet: Role of sodium/glucose Co-transporter inhibition in male mice

Obesity-related kidney disease (ORKD) is a progressive kidney disease secondary to obesity, in which lipid deposition in proximal tubule epithelial cells drives tubular damage and inflammation. Considering that sodium/glucose co-transporter 2 (SGLT2) inhibitors are known to modulate renal lipid metabolism, we investigated the effect of SGLT2 inhibition on the development of hyperpalatable diet-induced ORKD. Obesity was induced in male and female C57Bl/6 mice through the administration of a high sugar and butter diet (HSB diet) for 12 weeks. Both sexes exhibited increased body weight and adiposity in response to the HSB diet; however, only male mice developed significant renal and metabolic alterations. In males, the HSB diet induced: (1) fasting hyperglycemia and impaired glucose tolerance; (2) increased renal triglyceride levels; (3) reduced creatinine clearance (CCr), a surrogate marker of glomerular filtration rate (eGFR), and altered fluid balance; (4) tubular proteinuria; (5) histological evidence of tubular injury; and (6) elevated renal pro-inflammatory cytokine levels and tubulointerstitial cell infiltration. When indicated, mice were treated daily with 1 mg/kg of dapagliflozin (DAPA), an SGLT2 inhibitor, for 4 weeks. DAPA treatment effectively attenuated the renal and metabolic alterations induced by the HSB diet in male mice. These findings suggest that, in male mice, hyperpalatable diet-induced ORKD involves SGLT2-dependent renal lipid accumulation, which may contribute to tubular proteinuria, injury, and inflammation. This study provides new insights into the molecular mechanisms underlying ORKD and supports the therapeutic potential of SGLT2 inhibitors for its prevention or treatment.