mTOR blockade prevents progressive proteinuria but induces hyperglycaemia in obese Dahl salt-sensitive rats before...

Previous studies have demonstrated that mammalian target of rapamycin (mTOR) activity is significantly increased in the kidneys of Dahl salt-sensitive (SS) rats during the development of renal injury. Therefore, in the present study we examined whether blockade of mTOR with rapamycin inhibits renal injury in Dahl salt-sensitive leptin receptor mutant (SS^LepRmutant) rats. Four-week-old SS and SS^LepRmutant rats were treated with either vehicle (saline, i.p.) or rapamycin (1.5 mg/kg/day, i.p.) for 4 weeks. Body weight was significantly higher in SS^LepRmutant rats than in SS rats, and chronic treatment with rapamycin significantly decreased body weight only in SS^LepRmutant rats. In vehicle-treated rats, blood glucose levels were within the physiological range (≤120 mg/dL), and rapamycin treatment induced hyperglycaemia in SS^LepRmutant rats (550 ± 54 mg/dL). Additionally, plasma insulin was significantly increased in SS^LepRmutant rats versus SS rats, and rapamycin reduced plasma insulin in SS^LepRmutant rats. Proteinuria was significantly higher in SS^LepRmutant rats versus SS rats (564 ± 104 and 26 ± 12 mg/day, respectively), and rapamycin significantly decreased proteinuria in SS^LepRmutant rats (48 ± 18 mg/day). Moreover, SS^LepRmutant rats displayed renal hyperfiltration and marked glomerular and tubular injury compared with SS rats, and rapamycin improved these renal abnormalities in SS^LepRmutant rats. Interestingly, we observed that renal sodium glucose cotransporter 2 (SGLT2) expression was significantly elevated in SS^LepRmutant rats versus SS rats, and rapamycin markedly reduced renal SGLT2 expression in SS^LepRmutant rats. Overall, these data indicate that mTOR plays an important role in renal metabolic disease in obese SS^LepRmutant rats before puberty and suggest that rapamycin might prevent renal hyperfiltration associated with obesity by decreasing renal SGLT2 activity.