MTOR/S6K Signaling: A Novel Effector of Neuronal Action of Angiotensin II

Abstract

The renin‐angiotensin system (RAS) is critically involved in arterial pressure regulation. Angiotensin II (Ang II), the main effector of the RAS, acts in several brain nuclei including the subfornical organ (SFO) to increase arterial pressure by stimulating Ang II type 1 receptors (AT1R). However, the signaling mechanisms of neuronal AT1R remain poorly defined. Neuronal mammalian target of rapamycin (mTOR) and its downstream effector, p70S6 kinase (S6K), have emerged as important regulators of arterial pressure. Thus, we hypothesized that mTOR/S6K signaling mediates brain Ang II actions. In hypothalamic neuronal cell line (GT1‐7), transfected with AT1aR, Ang II (100 nM) caused a time‐dependent increase in S6K activity with a maximum effect at 15 min (3.4‐fold; P<0.05 vs. vehicle). Pre‐treatment with AT1R blocker (1 μM losartan) completely abolished Ang II‐induced activation of S6K. We also examined, by immunohistochemistry, the level of phospho‐S6 (a readout of S6K activity) in the brain of transgenic sRA mice which have overactive brain RAS. The SFO of female sRA mice exhibited significantly (P=0.02) elevated phospho‐S6 positive cells (64±6) relative to littermate controls (36±8). This increase was specific to the SFO as there was no difference in phospho‐S6 levels in other forebrain nuclei in sRA vs. control mice. This study has identified mTOR/S6K as a novel mechanism of AT1R signaling in neurons.