# Neural Mechanisms of Hypertension

> **NIH NIH R01** · UNIVERSITY OF NEVADA RENO · 2020 · $578,959

## Abstract

Project Summary/Abstract
 Despite recent advances in pharmacological therapy and patient care, cardiovascular disease (CVD)
remains a leading cause of morbidity and mortality. Salt-induced hypertension (SH) is a major form of human
primary hypertension, which is the main risk factor for CVD. This proposal is designed to elucidate neural
mechanisms underlying SH, with a focus on uncovering novel mechanisms involved in activating the brain
(pro)renin receptor (PRR) and renin-angiotensin system (RAS). Accumulating evidence underscores the
importance of neural mechanisms in SH, especially the centrality of brain RAS activity in the lamina terminalis
and the paraventricular nucleus (PVN) of the hypothalamus. We recently reported that up-regulation of the PRR
in the PVN is responsible for increased angiotensin II production, activation of the brain RAS and the
development of SH, suggesting that the PRR is a key link in the chain leading from high-salt intake to brain RAS
activation. However, how a high-salt diet up-regulates the brain RAS and PRR remains unknown. Our central
hypothesis is that high salt up-regulates the brain PRR through an epithelial sodium channel (ENaC) and reverse
mode Na+/Ca2+ exchanger (rNCX)–coupled signaling pathway, and modifies the central nervous system
epigenetically, leading to the development of SH.
 To test this hypothesis, we will employ two commonly used mouse models of experimental SH, in
conjunction with innovative techniques, including ex vivo live Ca2+ imaging, ground-state depletion followed by
individual molecule return (GSDIM) super-resolution microscopy, cell-specific PVN targeting, and telemetry
recording of phenotypes in vivo . Our objectives are to define the molecular signaling events that lead to
regulation of the brain RAS and to establish the functional significance of epigenetics in SH. The following specific
aims are proposed to address these objectives: (1) to test the hypothesis that formation of ENaC-rNCX–coupled
subcellular Ca2+ microdomains is responsible for up-regulation of the neuronal PRR in salt-induced hypertension,
and (2) to test the hypothesis that H3K4 trimethylation of the PRR promoter is crucial for the development of
salt-induced hypertension. The proposed research is conceptually innovative and highly significant because it
will resolve the enigma of how high salt intake activates the brain RAS and epigenetically modifies the PRR,
leading to the development of SH. Successful completion of this proposal will establish molecular mechanisms
of SH involving brain RAS activation and provide mechanistic insight into the epigenetics of hypertension.

## Key facts

- **NIH application ID:** 9988813
- **Project number:** 2R01HL122770-07
- **Recipient organization:** UNIVERSITY OF NEVADA RENO
- **Principal Investigator:** Scott Earley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $578,959
- **Award type:** 2
- **Project period:** 2014-12-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988813

## Citation

> US National Institutes of Health, RePORTER application 9988813, Neural Mechanisms of Hypertension (2R01HL122770-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988813. Licensed CC0.

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