Therapeutic Suppression of mTOR (Mammalian Target of Rapamycin) Signaling Prevents and Reverses Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats

摘要

mTOR (mammalian target of rapamycin) signaling has emerged as a key regulator in a wide range of cellularprocesses ranging from cell proliferation, immune responses, and electrolyte homeostasis. mTOR consists of 2 distinctprotein complexes, mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) with distinct downstream signalingevents. mTORC1 has been implicated in pathological conditions, such as cancer and type 2 diabetes mellitus in humans, andinhibition of this pathway with rapamycin has been shown to attenuate salt-induced hypertension in Dahl salt-sensitive rats.Several studies have found that the mTORC2 pathway is involved in the regulation of renal tubular sodium and potassiumtransport, but its role in hypertension has remained largely unexplored. In the present study, we, therefore, determinedthe effect of mTORC2 inhibition with compound PP242 on salt-induced hypertension and renal injury in salt-sensitiverats. We found that PP242 not only completely prevented but also reversed salt-induced hypertension and kidney injuryin salt-sensitive rats. PP242 exhibited potent natriuretic actions, and chronic administration tended to produce a negativeNa + balance even during high-salt feeding. The results indicate that mTORC2 and the related downstream associatedpathways play an important role in regulation of sodium balance and arterial pressure regulation in salt-sensitive rats.Therapeutic suppression of the mTORC2 pathway represents a novel pathway for the potential treatment of hypertension.