The brain renin-angiotensin system (RAS) plays a crucial role in regulating cardiovascular and metabolic function. Nuclei-specific synthesis and action of angiotensin-II (ANG) in the brain affords mechanisms for the independent regulation of fluid intake and sympathetic nerve activity (SNA) controlling blood pressure (BP) and metabolic responses. That angiotensinogen (AGT), the substrate for renin and precursor to ANG is constitutively released from glial cells throughout the brain, and from neurons in nuclei controlling cardiovascular and metabolic function, implores the central question of how ANG production in the brain is regulated? We identified an unexpected and novel mechanism regulating expression of renin in the brain which may address this. However, the initiating signals and mechanisms involved remains unknown. This project will examine the innovative concepts and hypotheses that: 1) there is coordinate regulation of renin mRNA isoforms which controls RAS activity in the brain, and 2) impairment of this novel control mechanism causes neurogenic hypertension and increases sensitivity of exposure to hypertension-causing stimuli. We will examine this original concept in the following two specific aims: 1) test the hypothesis that coordinated expression of Ren-b and Ren-a in the subfornical organ (SFO), paraventricular nucleus (PVN), and arcuate nucleus (ARC) mediates local ANG production and action which alters SNA controlling cardiovascular and metabolic function, and 2) test the hypothesis that disinhibition of Ren-a expression with concomitant inhibition of renin-b expression in the SFO, PVN and ARC is required to mediate sensitization of the hypertensive response (HTR) to mild humoral (e.g. ANG) and dietary (e.g. high fat diet) stressors. The studies will advance the concepts that a) Ren-b expression is an endogenous inhibitor of Ren-a expression limiting ANG production in the presence of excess extracellular AGT, and b) under conditions which threaten homeostasis (e.g. water deprivation) or in response to pathological stimuli (e.g. DOCA-salt or high fat diet), previously dormant Ren-a expression is disinhibited leading to site-specific prorenin activation, ANG generation and ANG action. Importantly, we hypothesize that impairment of this regulatory circuit causes neurogenic hypertension. The project has natural synergy as other projects that will similarly examine blood pressure and metabolic signaling in forebrain and hypothalamic nuclei. Moreover, this project will be informed by the data collected by the other projects and will synergize by exploring RAS-dependent and renin-dependent mechanisms in those systems.
The renin-angiotensin system (RAS) in the brain is an important regulator of the sympathetic nervous system and its dysregulation has been implicated in many forms of hypertension including neurogenic hypertension. However, how the activity of the brain RAS becomes dysregulated in, or as a precursor to hypertension remains a critical barrier toward its prevention and treatment. This proposal will examine the functional significance of a novel molecular mechanism for regulating brain RAS activity identified by us in the previous budget period, and the fundamental physiological mechanisms regulating brain RAS activity in hypertension and in response to hypertension-causing stressors.
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