# Inflammatory Nicotinic Acetylcholine Receptors in a Genetic Model of Essential Hypertension

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

Nearly half of US adults have hypertension. Hypertension is also highly prevalent in the VA Health
System. Traditionally, hypertension has been thought to be a function of abnormalities in the renal,
vascular, and nervous systems. In recent years, clinical and basic science data clearly demonstrate that
there is crosstalk between the nervous and immune systems, and the neuro-immune axis plays an integral
part in development of hypertension.
 The neuro-immune axis describes a regulatory, bidirectional interaction between the autonomic
nervous and immune systems. Activation of the nicotinic arm of this axis leads to both anti- and pro-
inflammatory immune responses. We discovered that activation of the nicotinic acetylcholine receptor with
nicotine (a non-selective agonist), both in vitro and in vivo, induces an inflammatory M1 macrophage
population that infiltrates the renal medulla and leads to the development of hypertension in the genetic
Spontaneously Hypertensive Rat (SHR) model of essential hypertension. Our long-term goal is to develop
novel therapeutic agents to target this cholinergic arm of the neuro-immune axis in human essential
hypertension. The short-term goal of this proposal is to identify the nicotinic acetylcholine receptors
involved in this cholinergic arm, and to explore their role in the development of essential
hypertension.
The central hypothesis of this proposal is that a specific arm of the nicotinic acetylcholine receptor-mediated
immune response favors inflammatory mechanisms to promote the development of hypertension. This
hypothesis is grounded in novel and exciting preliminary data showing that the alpha4beta2 subtype
of the nicotinic acetylcholine receptor is upregulated in immune cells in the SHR model of essential
hypertension, and that selective activation of the alpha4beta2nicotinic acetylcholine receptor leads
to the development of hypertension. Using state-of-the-art in vivo and in vitro molecular and cellular
approaches, as well as in vivo hemodynamics, this proposal will 1) determine the role of the
alpha4beta2 subtype of the nicotinic acetylcholine receptor in pro-inflammatory immune cells
responses; 2) explore whether the alpha4beta2 nicotinic acetylcholine receptor plays a causal role
in the development and maintenance of essential hypertension; and 3) examine whether splenic
innervation promotes expansion of immune cells endowed with the alpha4beta2 nicotinic
acetylcholine receptor, and thus an inflammatory phenotype, in essential hypertension.
Essential hypertension is the most prevalent cardiovascular condition in the VA Health System and
remains undertreated. Major gaps in our understanding of the neuro-immune axis limit our ability
to treat hypertension. This application provides a unique opportunity to better understand this axis
and may therefore open the door for new anti-hypertensive therapeutics.

## Key facts

- **NIH application ID:** 10254791
- **Project number:** 1I01BX005173-01A2
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Sailesh Harwani
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10254791

## Citation

> US National Institutes of Health, RePORTER application 10254791, Inflammatory Nicotinic Acetylcholine Receptors in a Genetic Model of Essential Hypertension (1I01BX005173-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10254791. Licensed CC0.

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