# Interleukin-21 and endothelial dysfunction in hypertension

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2020 · $30,231

## Abstract

PROJECT SUMMARY
Hypertension is the most common primary diagnosis in the United States, and even treated individuals remain
at elevated cardiovascular risk, suggesting that current therapeutic options are suboptimal. Emerging evidence
implicates activation of the immune system as a central feature of hypertension, particularly CD4+ T helper
lymphocytes and T cell-derived cytokines. Hypertension is characterized by infiltration of T lymphocytes into
end-organs such as the vasculature, kidney, and heart. Interleukin-21 (IL-21) is a pro-inflammatory cytokine
produced by multiple T helper subsets that potentiates IL-17A production by T helper cells. A recently
described CD4+ subset of T peripheral helper cells (TPH) cells were shown to produce IL-21 in the context of
autoimmune disease. IL-17A is a cytokine known to contribute to immune activation in hypertension and act
directly on the endothelium. Preliminary studies have shown that IL-21 deficient mice have a blunted
hypertensive response, and neutralization of IL-21 both reverses endothelial dysfunction and lowers blood
pressure in mice. This compelling evidence suggest that IL-21 is a key cytokine driving activation of the
adaptive immune system and end-organ damage in hypertension; however, which T cell subsets produce IL-21
in hypertension and whether IL-21 acts directly on the endothelium is unknown. This project will (a) test the
hypothesis that TPH cells are the primary source of IL-21 in hypertension and that IL-21 producing T cells are
sufficient to promote hypertension in vivo, (b) mechanistically determine the role of IL-21 in endothelial
dysfunction and (c) evaluate the long-term impact of cytokine-neutralizing therapy on clinical cardiovascular
outcomes. The completion of these studies will yield critical insights into the mechanism underlying immune
activation in hypertension and identify potential novel cellular targets.

## Key facts

- **NIH application ID:** 9908443
- **Project number:** 1F30HL151069-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Charles Duncan Smart
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,231
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908443

## Citation

> US National Institutes of Health, RePORTER application 9908443, Interleukin-21 and endothelial dysfunction in hypertension (1F30HL151069-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9908443. Licensed CC0.

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