SGLT2i combined with physical training attenuates metabolic dysfunction and pyroptosis-mediated renal cell death in diabetic kidney disease

Diabetic kidney disease (DKD) treatment remains a significant clinical challenge; however, despite the recently demonstrated benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i), the residual risk of progression is still present, and strategies involving combined interventions may provide additional benefits. We investigated the effects of SGLT2i (empagliflozin, 35 mg/kg/day) and moderate-intensity physical training (50-min sessions every 48 h at 60-80% of maximal velocity), both individually and in combination, on DKD progression. Male C57BL/6J mice exposed to a high-fat diet and a single dose of streptozotocin (40 mg/kg) were assigned to four groups (n = 12/group): Control, SGLT2i, physical training (PhTr), and SGLT2i + PhTr. Mice were evaluated over 25 weeks. Body mass, caloric intake, blood glucose, glomerular morphology, neutrophil gelatinase-associated lipocalin (NGAL) expression, oxidative stress markers, inflammatory cytokines, and inflammasome-pyroptosis axis were evaluated. At week 25, the SGLT2i + PhTr group exhibited significantly lower body mass than the Control group. SGLT2i and SGLT2i + PhTr demonstrated the most pronounced effects on blood glucose level reduction. All treatments improved glomerular morphology and reduced NGAL expression. SGLT2i treatment decreased oxidative stress markers in kidney tissue, whereas the combined therapy modulated inflammatory cytokines in skeletal muscle. All interventions reduced gasdermin D immunoexpression despite unchanged inflammasome components. These findings highlight distinct renal- and muscle-specific responses to SGLT2i and PhTr. Both single and combined interventions demonstrated distinct effects in experimental DKD, underscoring the potential benefits of a multimodal therapeutic approach.