# Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension

> **NIH NIH P01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $476,990

## Abstract

Summary/Abstract
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.

## Key facts

- **NIH application ID:** 10213809
- **Project number:** 5P01HL084207-14
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Curt Daniel Sigmund
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $476,990
- **Award type:** 5
- **Project period:** 2007-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213809

## Citation

> US National Institutes of Health, RePORTER application 10213809, Novel Mechanism Regulating RAS Activity in the Brain: Role in Neurogenic Hypertension (5P01HL084207-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10213809. Licensed CC0.

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