Abstract P003: Hyperactive Brain Renin Angiotensin System Induces Polydipsia Through mTORC1 Pathway
Mechanistic target of rapamycin complex 1 (mTORC1) is a molecular hub for signaling pathways mediating a wide range of cellular events involved in the regulation of various physiological and pathophysiological processes. We previously demonstrated that Angiotensin II (Ang II) activates mTORC1 and its downstream effector ribosomal protein S6 kinase in neurons in vitro. Here, we investigated the role of brain mTORC1 in hypertension and polydipsia induced by Ang II. In wild-type mice, acute stimulation of angiotensin type 1 receptor signaling by intracerebroventricular (ICV) injection of Ang II (1 μg, 30 min) activated mTORC1 signaling in the subfornical organ (SFO), a critical brain region in cardiovascular control and fluid balance, as indicated by the significant increase in the number of phosphorylated S6-positive cells (32±2 vs 13±3 in vehicle group). Similar upregulation of the mTORC1 pathway in the SFO was also found in the mice treated subcutaneously with Ang II (1000 ng/kg/min) using an osmotic minipump for 1 week (27±3 vs 11±2 in vehicle group). To verify functional roles of the Ang II activation of mTORC1 in the SFO, we utilized hypertensive and polydipsic transgenic mice (sRA) that have a hyperactive brain renin-angiotensin system, resulting in SFO-overproduction of Ang II. Interestingly, sRA mice exhibited substantially elevated phospho-S6 immunoreactivity only in the SFO (64±6 vs 36±8 in controls) but not in other cardiovascular regulatory regions including the paraventricular nucleus. ICV delivery of mTORC1 blocker, rapamycin (10 ng/day for 7 days) significantly (p<0.05) reduced daily water intake (-4.5±0.7 mL) compared to vehicle-treated sRA mice (-0.7±0.6 mL). In contrast, systolic blood pressure remained unchanged with rapamycin treatment (123±1 vs 125±4 mmHg in pre-treatment) and was consistently higher than the control group (110±4 mmHg). These results suggest that mTORC1 activity in the SFO is a critical determinant of the polydipsia evoked by Ang II.
Author Disclosures: K. Muta: None. D.A. Morgan: None. J.L. Grobe: None. C.D. Sigmund: None. K. Rahmouni: None.
- © 2015 by American Heart Association, Inc.