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mTOR blockade prevents progressive proteinuria but induces hyperglycaemia in obese Dahl salt‐sensitive rats before puberty

Year: 2025

Type: article

Abstract: 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 LepR mutant) rats. Four‐week‐old SS and SS LepR mutant 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 LepR mutant rats than in SS rats, and chronic treatment with rapamycin significantly decreased body weight only in SS LepR mutant rats. In vehicle‐treated rats, blood glucose levels were within the physiological range (≤120 mg/dL), and rapamycin treatment induced hyperglycaemia in SS LepR mutant rats (550 ± 54 mg/dL). Additionally, plasma insulin was significantly increased in SS LepR mutant rats versus SS rats, and rapamycin reduced plasma insulin in SS LepR mutant rats. Proteinuria was significantly higher in SS LepR mutant rats versus SS rats (564 ± 104 and 26 ± 12 mg/day, respectively), and rapamycin significantly decreased proteinuria in SS LepR mutant rats (48 ± 18 mg/day). Moreover, SS LepR mutant rats displayed renal hyperfiltration and marked glomerular and tubular injury compared with SS rats, and rapamycin improved these renal abnormalities in SS LepR mutant rats. Interestingly, we observed that renal sodium glucose cotransporter 2 (SGLT2) expression was significantly elevated in SS LepR mutant rats versus SS rats, and rapamycin markedly reduced renal SGLT2 expression in SS LepR mutant rats. Overall, these data indicate that mTOR plays an important role in renal metabolic disease in obese SS LepR mutant rats before puberty and suggest that rapamycin might prevent renal hyperfiltration associated with obesity by decreasing renal SGLT2 activity.

Source: Experimental Physiology

DOI: 10.1113/ep092435