Inhibition of mTORC1 signaling pathway attenuates the salt‐induced hypertension in Dahl SS rats

Abstract

The kidney plays a key role in blood pressure regulation and can be significantly compromised by oxidative stress. In the Dahl SS rat model, high salt intake leads to an increase in the production of ROS including superoxide O·2 and H2O2 in the kidney by stimulating NADPH oxidase. Over the last decade, the mammalian target of rapamycin (mTOR) signaling pathway has emerged as a key regulator in a wide range of cellular processes such as cell cycle progression, hypertrophy, cell survival and Na+ reabsorption. The ability of mTOR signaling to sense and integrate various signals including H2O2 raises the possibility that mTOR may serve as a “molecular hub” that allows nephron segments to integrate various inputs for the development of salt‐sensitive hypertension, Na+ homeostasis and kidney injury. Remarkably, little is known about the association of the mTOR pathway to the pathophysiology of hypertension. The goal of the present study is to explore the inhibition of elevations of renal perfusion pressure (RPP) upon H2O2 mediated upregulation of mTORC1 attenuates the salt‐induced hypertension by inhibiting immune cells infiltration/proliferation, hypertrophy and kidney injury. We observed significant upregulation of pS6/S6 which is readout for mTORC1 activity in renal cortex and pAKT/AKT which is readout of mTORC2 activity in renal outer medulla of SS rats fed a 4.0% NaCl diet for 21 days. Our in vitro data suggested that isolated nephron segments treated with H2O2 can upregulate the mTOR signaling pathway. An FDA approved drug rapamycin (1.5 mg/Kg per day, ip) which specifically binds and inhibits mTORC1, administrated daily to 10 weeks old SS rats fed a 4.0% NaCl diet for 21 days significantly reduced mean arterial blood pressure (from 176 ± 9 to 153 ± 12 mmHg) and urine albumin/creatinine ratio (from 13.42 ± 6.47 to 4.13 ± 1.09) compared to vehicle treated SS rats. Rapamycin treated rats also exhibited significantly reduced hypertrophy index (kidney wt/body wt), proliferating cells (Ki67 positive cells) without increasing the apoptotic cells, T lymphocytes (CD3+/mm2 from 191.64 ± 77.83 to 80.39 ± 14.34 and 236.87 ± 70.40 to 71.02 ± 15.81 in renal cortex and outer medulla, respectively) and macrophages (ED1+/mm2 from 605.40 ± 149.94 to 253.65 ± 82.96 and 483.60 ± 275.33 to 204.43 ± 85.13 in renal cortex and outer medulla, respectively). These results demonstrate that the inhibition of mTORC1 attenuates the salt‐induced hypertension and infiltration of immune cells into the kidney. This study for the first time demonstrated that the mTOR inhibitor could be a potential therapeutic agent to attenuate salt‐induced hypertension.