Abstract
Recently, we reported that obese Dahl salt-sensitive leptin receptor mutant (SS(LepR)mutant) rats develop glomerular injury and progressive proteinuria prior to puberty. Moreover, this early progression of proteinuria was associated with elevations in GFR. Therefore, the current study examined whether treatment with lisinopril to reduce GFR slows the early progression of proteinuria in SS(LepR)mutant rats prior to puberty. Experiments were performed on 4-week-old SS and SS(LepR)mutant rats that were either treated with vehicle or lisinopril (20 mg/kg/day, drinking water) for 4 weeks. We did not observe any differences in MAP between SS and SS(LepR)mutant rats treated with vehicle (148 ± 5 vs. 163 ± 6 mmHg, respectively). Interestingly, chronic treatment with lisinopril markedly reduced MAP in SS rats (111 ± 3 mmHg) but had no effect on MAP in SS(LepR)mutant rats (155 ± 4 mmHg). Treatment with lisinopril significantly reduced proteinuria in SS and SS(LepR)mutant rats compared to their vehicle counterparts (19 ± 5 and 258 ± 34 vs. 71 ± 12 and 498 ± 66 mg/day, respectively). Additionally, nephrin excretion was significantly elevated in SS(LepR)mutant rats versus SS rats, and lisinopril reduced nephrin excretion in both strains. GFR was significantly elevated in SS(LepR)mutant rats compared to SS rats, and lisinopril treatment reduced GFR in SS(LepR)mutant rats by 30%. The kidneys from SS(LepR)mutant rats displayed glomerular injury with increased mesangial expansion and renal inflammation versus SS rats. Chronic treatment with lisinopril significantly decreased glomerular injury and renal inflammation in the SS(LepR)mutant rats. Overall, these data indicate that inhibiting renal hyperfiltration associated with obesity is beneficial in slowing the early development of glomerular injury and renal inflammation.