Empagliflozin preserves mitochondrial function and reduces tubular injury in obese type 2 diabetic ZSF-1 rats

Diabetic nephropathy remains the leading cause of end-stage renal disease. The ZSF-1 rat model combines features known as the metabolic syndrome, such as type 2 diabetes mellitus, hypertension and obesity, developing progressive kidney disease. In this study, we investigated the nephroprotective mechanisms of the SGLT2 inhibitor empagliflozin, focusing on mitochondrial function. Obese ZSF-1 rats were randomized at 24 weeks of age to receive either placebo or empagliflozin for eight weeks, while lean ZSF-1 rats served as healthy controls. Kidney function, assessed by glomerular filtration rate (GFR), was significantly reduced in obese rats and was not improved by empagliflozin treatment. However, obese animals exhibited increased tubular injury, tubular cast formation, and elevated total and tubular proteinuria, all of which were attenuated by empagliflozin. Mitochondrial function was evaluated in freshly isolated cortical kidney mitochondria by measuring oxygen consumption. Obese ZSF-1 rats showed impaired respiratory capacity and reduced protein expression of oxidative phosphorylation (OXPHOS) complexes II, III, IV, and V, indicating mitochondrial dysfunction. Empagliflozin treatment improved mitochondrial function by enhancing complex I- and IV-linked respiration and restoring the expression of OXPHOS complexes II, III, and IV. In addition, empagliflozin treatment was linked to improved mitochondrial dynamics and modulation of autophagic activity, suggesting enhanced mitochondrial quality control. Overall, these findings demonstrate that empagliflozin exerts nephroprotective effects primarily at the tubular level in obese ZSF-1 rats. The beneficial effects appear to be mediated through improved mitochondrial function, enhanced mitochondrial integrity, and reduced tubular injury.