Essential role of mTORC1 in the hypertension induced by overactivation of the brain renin‐angiotensin system (1067.2)

Abstract

Angiotensin II (Ang II) is a major effector peptide of the renin‐angiotensin system (RAS). Ang II‐induced activation of angiotensin type 1 receptor (AT1R) signaling in cardiovascular‐related brain nuclei such as the subfornical organ (SFO) is thought to be important for the development of hypertension. However, the molecular machinery underlying the central pressor actions of Ang II is poorly defined. We previously demonstrated the involvement of neuronal mammalian target of rapamycin complex 1 (mTORC1) in blood pressure (BP) regulation. Interestingly, using in vitro systems we also found that mTORC1 is a downstream element of neuronal AT1R signaling. To assess the relevance of mTORC1 for Ang II action, we first examined mTORC1 activity in the cardiovascular brain regions in hypertensive transgenic mice with brain‐specific hyperactive RAS (sRA mice). Strikingly, the number of phospho‐S6 positive cells (used as a readout of mTORC1 activity) was significantly higher in the SFO of sRA mice (64±6) relative to controls (36±8, p<0.05, n=5). Moreover, central administration of an adenovirus encoding a dominant negative S6 kinase (an mTORC1 substrate) lowered systolic BP in sRA (from 148±8 to 130±8 mmHg, p<0.05, n=3) to comparable levels as control mice receiving GFP adenovirus (from 125±7 to 126±1 mmHg, n=3). These results indicate that neuronal mTORC1 activation is a critical event in brain RAS‐induced BP elevation.