LAUSR

Prepubertal obesity (PPO) is a public health problem that is now associated with renal injury. Recently, we reported that the obese SSLepRmutant rat develops inflammation and renal injury before puberty. Moreover, the progression of renal disease in the SSLepRmutant rat is associated with the increased renal expression of the mammalian target of rapamycin (mTOR). Previous studies have shown that the mTOR pathway contributes to inflammation and renal disease. Therefore, this study tested the hypothesis that rapamycin (a mTOR inhibitor) will attenuate renal inflammation and early progressive renal injury in SSLepRmutant rats. Four-week-old SS and SSLepRmutant rats were treated with either vehicle (saline) or rapamycin (1.5 mg/kg/day, ip) for 4 weeks. At baseline, body weight was significantly higher in SSLepRmutant vs SS rats and remained elevated throughout the study. Treatment with rapamycin significantly decreased body weight in SSLepRmutant rats without affecting SS rats. While blood glucose levels were in the normal physiological range throughout the study in SSLepRmutant and SS rats (≤120 mg/dL), treatment with rapamycin only increased blood glucose in SSLepRmutant rats (561±54 mg/dL) without affecting SS rats (116±23 mg/dL). At the end of the study, we observed significant elevations in plasma insulin in SSLepRmutant vs SS rats, and treatment with rapamycin significantly decreased insulin levels by >50% in SSLepRmutant rats. At baseline proteinuria was significantly higher in SSLepRmutant vs SS rats (72±52 vs. 6±6 mg/day), and it remained higher throughout the study (500±125 vs. 26±12 mg/day). Interestingly, treatment with rapamycin only decreased proteinuria in SSLepRmutant rats (62±8 mg/day). Glomerular injury and renal fibrosis were markedly greater in SSLepRmutant vs SS rats, and treatment with rapamycin ameliorated these histological changes. At the end of the study, we observed increased GFR (via creatinine clearance) in SSLepRmutant vs SS rats (3.93±0.5 vs. 0.56±0.2 mL/min/gkwt), and treatment with rapamycin reduced GFR in SSLepRmutant rats (0.47±0.1 mL/min/gkwt). While there were no detectable differences in the renal expression of IL-4 in SSLepRmutant vs SS rats, there was a significant decrease in the renal expression of IL-10 in SSLepRmutant vs SS rats. Treatment with rapamycin significantly increased the renal expression of IL-4 and IL-10 in SSLepRmutant rats, while not affecting SS rats. In conclusion, although rapamycin causes hyperglycemia, it prevents early progressive proteinuria by reducing GFR and increasing renal anti-inflammatory cytokines during PPO. Funding: 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.