Kidney Week

Abstract: SA-PO1176

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

Session Information

• CKD: Mechanisms - 3
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Mandal, Sautan, The University of Mississippi Medical Center, Jackson, Mississippi, United States

Sautan Mandal, DVM

• Bhopatkar, Anukool A., The University of Mississippi Medical Center, Jackson, Mississippi, United States

Anukool A. Bhopatkar, PhD

• Ekperikpe, Ubong S., The University of Mississippi Medical Center, Jackson, Mississippi, United States

Ubong S. Ekperikpe, MS, PhD

• Hoang, Ngoc, The University of Mississippi Medical Center, Jackson, Mississippi, United States

Ngoc Hoang, PhD

• Brooks, Karen, The University of Mississippi Medical Center, Jackson, Mississippi, United States

Karen Brooks

• Edwards, Kristin, The University of Mississippi Medical Center, Jackson, Mississippi, United States

Kristin Edwards, PhD

• Williams, Jan Michael, The University of Mississippi Medical Center, Jackson, Mississippi, United States

Jan Michael Williams, PhD

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 (SS^LepRmutant) 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 SS^LepRmutant rats before puberty. This suggests there may be energy metabolic alterations in the PTs of young SS^LepRmutant 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 SS^LepRmutant rats.

Methods

Four-week-old SS and SS^LepRmutant 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 SS^LepRmutant vs SS rats (401±51 vs. 27±4 mg/day; p<0.05), and treatment with EMPA reduced proteinuria in SS^LepRmutant rats (252±23 mg/day; p<0.05). We observed a 3-fold increase in GFR in SS^LepRmutant rats compared to SS rats, and EMPA markedly decreased GFR in SS^LepRmutant rats by 50%. Renal cortical FAO was reduced and PT glycolysis was increased in SS^LepRmutant 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 SS^LepRmutant rats.

Conclusion

Overall, these data indicate that the early proteinuria observed in SS^LepRmutant 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