# The role of the innate immune cell cyclooxygenase/prostaglandin system in blood pressureregulation

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $677,837

## Abstract

Systemic hypertension is a leading worldwide cause of morbidity and mortality. Salt-sensitivity is seen in
over half of affected individuals with systemic hypertension as well in significant numbers of normotensive
individuals at risk for subsequent development of hypertension. The etiology of “essential” hypertension is
multifactorial and has been described as a “mosaic”, but numerous studies indicate an important role for both
the adaptive and the innate immune systems in mediation of salt-sensitivity by affecting both kidney and
vasculature in hypertension development and/or exacerbation. The studies proposed in this application will
investigate novel interactions of the myeloid cyclooxygenase (COX)/prostaglandin system with the adaptive
immune system and mechanisms by which this interaction can mediate regulation of kidney salt handling and
hemodynamic responses to dietary salt.
 Myeloid cells of the innate immune system, especially macrophages and dendritic cells, are known to be a
rich source of prostaglandins. Prostaglandins, and specifically PGE2, can act as immune modulators and affect
both macrophage/dendritic cell and T cell function. Cyclooxygenase is the rate limiting step in the synthesis of
prostaglandins from arachidonic acid, and cyclooxygenase 2 (COX-2) is the predominant inducible isoform in
myeloid cells. We previously found that PGE2 is the predominant prostaglandin produced by COX-2 in kidney
myeloid cells (macrophages and dendritic cells), and myeloid COX-2 deficiency leads to a proinflammatory
(“M1”) phenotype while COX-2-mediated activation of the PGE2 receptor, PTGER2/EP4, promotes a non-
inflammatory, alternatively activated (“M2”) phenotype. Experimental and epidemiologic evidence link inhibition
or abnormalities in the cyclooxygenase/prostaglandin system to the pathogenesis or exacerbation of
hypertension. Our previous studies demonstrated that COX-2-derived prostaglandins from myeloid cells of the
innate immune system are important mediators of kidney salt and water balance. Wild type mice transplanted
with COX-2-/- bone marrow exacerbated increases in high salt-induced blood pressure. However, our previous
studies did not elucidate the mechanisms mediating these blood pressure alterations. We now find that mice
with selective myeloid deletion of COX-2 have increased hypertension and T cell kidney infiltration in response
to a high salt diet, but myeloid COX-2-/- mice crossed with mice with the Rag-1 deletion, which lack mature
lymphocytes, fail to increase blood pressure. These results indicate a potential role for myeloid COX-2 activity
to decrease T cell activation in response to a high salt diet. In the present studies, Aim I will investigate
alterations in T cell phenotype in response to myeloid deletion of COX-2 alterations in T cell-mediated increases
in kidney sodium reabsorption and/or directly activates kidney sodium transporters. Aim II will determine the
role of myeloid COX-2 activity to activate the PD-L...

## Key facts

- **NIH application ID:** 10977961
- **Project number:** 2R01DK062794-20A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RAYMOND C. HARRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $677,837
- **Award type:** 2
- **Project period:** 2002-12-20 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10977961

## Citation

> US National Institutes of Health, RePORTER application 10977961, The role of the innate immune cell cyclooxygenase/prostaglandin system in blood pressureregulation (2R01DK062794-20A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10977961. Licensed CC0.

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