Abstract
Recently, we reported that obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) 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 SSLepRmutant rats prior to puberty. Experiments were performed on 4-week-old SS and SSLepRmutant 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 SSLepRmutant 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 SSLepRmutant rats (155 ± 4 mmHg). Treatment with lisinopril significantly reduced proteinuria in SS and SSLepRmutant 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 SSLepRmutant rats versus SS rats, and lisinopril reduced nephrin excretion in both strains. GFR was significantly elevated in SSLepRmutant rats compared to SS rats, and lisinopril treatment reduced GFR in SSLepRmutant rats by 30%. The kidneys from SSLepRmutant 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 SSLepRmutant 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.
Highlights
MATERIALS AND METHODSObesity has emerged as an epidemic and major health problem over the last few decades and has been linked to the increasing prevalence of renal disease (Chagnac et al, 2000; Bosma et al, 2004; Ejerblad et al, 2006; Hsu et al, 2006; Jacobs et al, 2010)
At the end of the study, body weight was significantly higher in SSLepRmutant rats compared to SS rats treated with vehicle (365 ± 15 and 276 ± 16 g, respectively), and treatment with lisinopril had no effect on body weight in either strain (388 ± 13 and 245 ± 10 g, respectively)
These functional changes in renal hemodynamics lead to increased transmission of systemic pressure to the glomerulus, which causes damage to the glomerular filtration barrier leading to proteinuria
Summary
Obesity has emerged as an epidemic and major health problem over the last few decades and has been linked to the increasing prevalence of renal disease (Chagnac et al, 2000; Bosma et al, 2004; Ejerblad et al, 2006; Hsu et al, 2006; Jacobs et al, 2010). Recent studies suggest that childhood obesity is associated with the increased risk of proteinuria in children independent of diabetes and hypertension (Ogden et al, 2016; Hales et al, 2017) indicating that renal dysfunction starts long before elevations in blood glucose levels and arterial pressure. We recently observed that the early progression of proteinuria in obese SSLepRmutant rats was associated with renal hyperfiltration (McPherson et al, 2020). The rats were anesthetized and terminal blood samples were taken from the abdominal aorta for the measurement of plasma total cholesterol concentrations determined by ELISA (Cayman Chemical Company, Ann Arbor, MI) Female rats in each group are represented by partially filled symbols
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