Treatment with Lisinopril Delays the Early Progression of Proteinuria in a Novel Model of Prepubertal Obesity

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Prepubertal childhood obesity (PPO) has emerged as an epidemic and major health problem in the United States. Recent studies suggest that PPO is associated with increased risk of renal injury in children. Approximately 37% of obese children develop microalbuminuria. However, an understanding of the mechanisms involved in PPO‐mediated renal disease remains unclear. Recently, we reported that the Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant – PPO model) strain develops proteinuria and podocyte injury independent of hyperglycemia and elevations in arterial pressure prior to puberty. Since renal hyperfiltration is a major characteristic of the early development of proteinuria associated with obesity, the current study determined the time course changes of glomerular filtration rate (GFR) in our model of PPO, the SSLepRmutant rat. GFR was significantly elevated in the PPO model compared to values measured to lean Control rats at 6 weeks of age indicating renal hyperfiltration (2.87±0.29 vs. 2.03±0.25 mL/min/gkwt, respectively). By 18 weeks of age, GFR decreased by 74% in the PPO model and by 46% in Control rats. The standard care of treatment for obese children with hypertension and increased risk of renal disease is lisinopril, an angiotensin converting enzyme inhibitor (ACEi). Therefore, the next set of experiments examined whether treatment with lisinopril prevents the early development of proteinuria and podocyte injury in the PPO model. Experiments were performed on four week‐old Control and PPO rats that were either treated with vehicle or lisinopril (20 mg/kg/day, drinking water) for four weeks. Protein excretion was significantly higher in the PPO model compared to Control rats at baseline (130±29 vs. 14±3 mg/day, respectively) and remained elevated during the course of the study (661±107 vs. 54±10 mg/day, respectively). While treatment with lisinopril had no effect on the progression of proteinuria in Control rats, it reduced protein excretion by 50% in the PPO model by the end of the study. In conclusion, these data indicate that our novel model of PPO, the SSLepRmutant strain, develops proteinuria associated with hyperfiltration at an early age that ultimately progresses to chronic kidney disease later in life. Moreover, treatment with lisinopril slowed the progression of proteinuria in the PPO model indicating that the renin‐angiotensin system plays an important role in the progression of proteinuria during PPO.Support or Funding InformationThis work was supported by funding from PhRMA predoctoral fellowship and the NIH/NIDDK Award Number 1 F31 DK109571‐01 awarded to K.C.M and AHA SDG 12SDG9440034 and by the NIGMS of the National Institutes of Health under Award Number P20GM104357 awarded to J.M.W.