Treatment with rapamycin reduces progressive proteinuria while inducing hyperglycemia in obese Dahl salt‐sensitive leptin‐receptor mutant rats prior to puberty

Abstract

Prepubertal obesity (PPO) is now considered a risk factor for the development of proteinuria and renal injury in children. Recently, we observed the early development of renal injury in the obese SSLepRmutant strain is associated with elevations in GFR and glomerular injury prior to puberty. However, the mechanisms involved remain unclear. The mammalian target of rapamycin (mTOR) signaling pathway has been shown to contribute to various forms of renal disease. In the current study, we examined whether treatment with the mTOR inhibitor, rapamycin, reduces the early progression of renal injury in SSLepRmutant rats during PPO. Four week‐old SS and SSLepRmutant rats were treated with either vehicle (saline) or rapamycin (1.5 mg/kg/day, ip) until rats reached 8 weeks of age. At baseline, body weight was significantly higher in vehicle‐treated SSLepRmutant rats compared to SS rats and remained elevated over the course of the study (309±13 vs. 219±27 g, respectively). Treatment with rapamycin significantly reduced body weight in SSLepRmutant rats compared to vehicle SSLepRmutant rats (206±9 g). At baseline, non‐fasting blood glucose levels were similar in both SS and SSLepRmutant rats and were within normal physiological range (≤120 mg/dl). Interestingly, chronic treatment with rapamycin markedly increased blood glucose levels in SSLepRmutant rats vs. vehicle SSLepRmutant rats (438±8 vs. 123±5 mg/dl, respectively) but had no effects in SS rats. At the end of the study, plasma insulin levels were significantly elevated in vehicle‐treated SSLepRmutant rats compared to the values measured in SS rats (6±1 vs. 1±0.6 ng/dl, respectively), and rapamycin treatment only reduced plasma insulin in SSLepRmutant (2±0.7 ng/dl, respectively). At baseline, proteinuria was significantly higher in SSLepRmutant rats compared to SS rats (159±34 and 17±7 mg/day, respectively) and remained elevated throughout the study (558±79 and 73±34 mg/day, respectively). By the end of the study, rapamycin significantly reduced proteinuria in SSLepRmutant rats (225±67 mg/day). We observed a significant increase in creatinine clearance (CCr) in SSLepRmutant rats vs SS rats indicating increased GFR (4.0±0.6 vs. 0.9±0.1 ml/min, respectively). Chronic treatment with rapamycin significantly decreased CCr in SSLepRmutant rats (2.2±0.9 ml/min) while not affecting SS rats. Overall, these data suggest that treatment with rapamycin is effective in reducing progressive proteinuria via reducing GFR while reducing plasma insulin levels and contributing to hyperglycemia in obese SSLepRmutant rats.