# Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension

> **NIH NIH R01** · EAST CAROLINA UNIVERSITY · 2020 · $368,750

## Abstract

Project Summary/Abstract
Hypertension (HTN) remains an important medical and public health issue in the United States. Most current
therapeutic measures are targeted against the peripheral renin-angiotensin system (RAS). These therapies have
reduced the morbidity and mortality in hypertensive patients. However, the long-term prognosis in patients with
hypertension remains poor, and new therapeutic approaches are needed. We previously showed that inhibiting
brain ADAM17 (A Disintegrin and Metalloprotease) or angiotensin II type 1 receptor (AT1R) upregulation will
reduce the progression of HTN. Our recent work indicates that kinin B1 receptor (B1R) activation leads to
elevated inflammation in key autonomic brain regions such as the hypothalamic paraventricular nucleus (PVN)
and pharmacological blockade or genetic deletion of B1R attenuates neurogenic HTN. In addition, our
preliminary data shows that B1R expression is elevated in the PVN of hypertensive human subjects. Evidence
suggests that elevated kininase I (carboxypeptidase, CPN/CPM that cleaves bradykinin into des-Arg9-
bradykinin, an endogenous agonist for B1R) levels account for increasing endogenous levels of B1R agonists,
leading to subsequent upregulation and activation of B1R. Stimulation of B1R results in ADAM17 activation that
in turn transactivates epidermal growth factor receptor (EGFR). However, the exact signal transduction
mechanisms of B1R and Kininase I, and interactions of AT1R, ADAM17 and EGFR with B1R, in HTN are not
clear. Therefore, in this proposal, we test the central hypothesis that the blockade of B1R signaling in the brain
reduces inflammation and oxidative stress, thereby decreasing sympathoexcitation, leading to attenuation of
neurogenic HTN. This hypothesis will be tested by following specific aims: (1) Determine whether targeted
blockade of B1R signaling attenuates neurogenic HTN, (2) Identify the causal role of central B1R activation to
the development of neurogenic HTN, and (3) Elucidate the signaling mechanisms and functional interactions
between B1R and AT1R/ADAM17/EGFR in the PVN in neurogenic HTN. In terms of approaches, we will use
state-of-the-art in vitro and in vivo pharmacological and molecular methods combined with novel and unique
genetic models to investigate the signaling mechanisms of B1R in HTN. This project will identify novel and vital
role of B1R signaling in HTN and provide insights for developing new therapeutics for the treatment of human
neurogenic HTN.

## Key facts

- **NIH application ID:** 10028541
- **Project number:** 1R01HL153115-01
- **Recipient organization:** EAST CAROLINA UNIVERSITY
- **Principal Investigator:** Srinivas Sriramula
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,750
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10028541

## Citation

> US National Institutes of Health, RePORTER application 10028541, Neuroimmune Mechanisms of Kinin B1 Receptor in Hypertension (1R01HL153115-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10028541. Licensed CC0.

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