The SGLT2 inhibitor, empagliflozin reduces early progressive proteinuria in obese SS rats

Abstract

Childhood/prepubertal obesity (PPO) is a world-wide epidemic and is considered a risk factor for renal injury. Therefore, there is a need to control this trend to decrease the future risk of chronic kidney disease. Recently, we reported that the SS LepR mutant rat is a novel model to study the mechanisms of renal injury associated with PPO. The SS LepR mutant rat develops progressive renal injury in the absence of hyperglycemia before puberty. SGLT2 inhibitors have been demonstrated to exert renoprotective effects independent of lowering blood glucose. Therefore, the objective of this study was to determine the effects of SGLT2 blockade with empagliflozin on the early progression of proteinuria in SS LepR mutant rats, during PPO. Four-week-old SS and SS LepR mutant rats (n = 5/group) were either treated with vehicle (diet) or empagliflozin (30 mg/kg/day, orally) for four weeks. While the SS LepR mutant rats had significantly higher body weights vs SS rats, there were no detectable differences in body weight or blood glucose levels in response to empagliflozin treatment in SS LepR mutant rats. We observed a significant increase in plasma insulin in control SS LepR mutant rats vs SS rats (7±1 vs 1±0.3 ng/mL, respectively, p<0.05), and treatment with empagliflozin did not have any effect on plasma insulin in SS LepR mutant rats (8±2 ng/mL). At baseline, we did not observe any significant difference in urine flow rate between control SS LepR mutant vs SS rats. After two weeks of treatment, while there was no observed difference in urine flow rate between SS LepR mutant and SS rats (17±3 ml/day vs 18±2 ml/day, respectively), empagliflozin significantly increased urine flow rate in SS LepR mutant rats (29±4 ml/day, p<0.05), but not in SS rats (17±3 ml/day). At baseline, we observed a difference in proteinuria between control SS LepR mutant vs SS rats (68±11 vs 6±3 mg/day, respectively, p<0.05), which remained elevated over the course of the study (471±75 vs 32±5 mg/day, respectively, p<0.05). Treatment with empagliflozin significantly decreased proteinuria in SS LepR mutant rats (223±52 mg/day, p<0.05) without affecting SS rats (27±8 mg/day). At the end of the study, we observed a significant increase in GFR in control SS LepR mutant rats vs SS rats (2.4±0.6 vs 0.5 mL/min/gkwt, respectively, p<0.05). Treatment with empagliflozin only significantly reduced GFR in SS LepR mutant rats (0.9±0.2 mL/min/gkwt, p<0.05). In conclusion, these data suggest that empagliflozin attenuates renal hyperfiltration and confers renoprotective effects during the early progression of renal disease associated with PPO. DK109133 and HL151407 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.