Empagliflozin Reduces Progressive Proteinuria by Potentially Reprogramming Energy Metabolism in Proximal Tubules in Young, Nondiabetic, Obese, Dahl Salt-Sensitive Rats

Background: Prepubertal obesity has become a major health problem and has been associated with early signs of proteinuria. Recently, we reported that the non-diabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) rat develops proteinuria prior to puberty. Renal proximal tubules (PTs) are highly energy demanding primarily relying on fatty acid oxidation (FAO) for energy production. Previous studies have demonstrated that PT energy metabolism shifts to glycolysis during the development of diabetic renal injury. We recently observed the expression of SGLT2 was upregulated in the PTs of SSLepRmutant rats before puberty. This suggests there may be energy metabolic alterations in the PTs of young SSLepRmutant rats contributing to proteinuria. Therefore, the current study examined whether treatment with the SGLT2i, empagliflozin (EMPA), shifts energy metabolism in the PT and reduces the early proteinuria in SSLepRmutant rats. Methods: Four-week-old SS and SSLepRmutant rats were treated with either vehicle (orally) or EMPA (30mg/kg/day) for 4 weeks. Proteinuria was measured every two-weeks. At the end of the protocol, one kidney was used to measure mitochondrial bioenergetics, and PTs were isolated from the other kidney to measure glycolysis. Results: Proteinuria was significantly higher in SSLepRmutant vs SS rats (401±51 vs. 27±4 mg/day; p<0.05), and treatment with EMPA reduced proteinuria in SSLepRmutant rats (252±23 mg/day; p<0.05). We observed a 3-fold increase in GFR in SSLepRmutant rats compared to SS rats, and EMPA markedly decreased GFR in SSLepRmutant rats by 50%. Renal cortical FAO was reduced and PT glycolysis was increased in SSLepRmutant rats when compared to SS rats suggesting a shift in the source of energy metabolism in PTs. Chronic treatment with EMPA significantly increased FAO in the renal cortex and markedly decreased glycolysis in the PTs in SSLepRmutant rats. Conclusion: Overall, these data indicate that the early proteinuria observed in SSLepRmutant rats during PPO is associated with an energy metabolic shift in PTs that may involve increased SGLT2 activity. Moreover, these results also suggest that SGLT2 inhibition could be of great potential in non-diabetic obese children with early signs of proteinuria. Funding: NIDDK Support