# Immune Modulation in Hypertension

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $634,453

## Abstract

PROJECT SUMMARY
Hypertensive stimuli activate innate and adaptive immune cells which then act on target organs such as the
kidney and vasculature causing tissue injury/inflammation and hypertensive end-organ damage. We and others
have shown that depleting subsets of immune cells or individual cytokines in rodent models is indeed protective
against these deleterious effects of hypertension. Yet there are currently no immunomodulatory therapies for
hypertension, which affects nearly 50% of adults worldwide. A major reason for this is that immunosuppressive
therapies would render a large percentage of people susceptible to infection and malignancy. A final common
pathway of immune activation in experimental and human hypertension is the skewing of T cell subsets towards
pro-inflammatory T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A) and IL-21, and away from anti-
inflammatory regulatory T cells (Treg). There is emerging evidence that Rho-associated protein kinase 2
(ROCK2) acts as a molecular switch in T helper cells by promoting Th17 differentiation, via phosphorylation of
STAT3 and IRF4, and inhibiting Treg differentiation. In this proposal, we will test the novel hypothesis that
hypertension is associated with activation of a ROCK2/STAT3/IRF4 pathway in T cells that leads to increased
Th17/Treg ratios and exacerbated hypertension and inflammatory damage. Furthermore, we propose that
selectively inhibiting ROCK2 will restore a homeostatic T cell balance without causing global
immunosuppression. A novel orally bioavailable selective ROCK2 inhibitor, KD025, has completed phase 2/3
clinical trials for IL-17A/IL-21 mediated autoimmune diseases with a favorable safety profile and no apparent
increased risk of infection. We have novel preliminary data that KD025 significantly reduces BP and increases
Treg/Th17 cell ratios in the kidney in response to experimental hypertension. In Aim 1 of this proposal, we will
use inducible conditional ROCK2 deficient mice to determine cell-specific roles of ROCK2 in hypertension. To
determine whether T cell ROCK2 deletion restores the Th17/Treg balance in hypertension with minimal effects
on other cell types, we will use a novel single cell technique, called CITE-Seq, to phenotype circulating leukocytes
as well as perform functional assays of immune function using a lipopolysaccharide (LPS) model of systemic
inflammation. In Aim 2, we will determine the effect of KD025 on BP, Th17/Treg balance, end-organ damage,
and LPS-induced inflammation in response to hypertensive stimuli. In Aim 3, we will use peripheral blood T cells
from normotensive and hypertensive humans to determine whether T cell ROCK2 activity is increased in
hypertension. To determine causality, we will adoptively transfer T cells from humans into immunodeficient mice
to determine whether human T cells promote hypertension and renal/vascular inflammation in a ROCK2
dependent manner in humanized mice. Our team is uniquely poised to condu...

## Key facts

- **NIH application ID:** 10521590
- **Project number:** 1R01HL161212-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Meenakshi Swaminathan Madhur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $634,453
- **Award type:** 1
- **Project period:** 2022-06-10 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521590

## Citation

> US National Institutes of Health, RePORTER application 10521590, Immune Modulation in Hypertension (1R01HL161212-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10521590. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*