# The Role of Cyclooxygenase-2 in Salt-Sensitive Hypertension

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $623,727

## Abstract

Essential hypertension is a major source of morbidity and mortality in the general population, and a
significant percentage of hypertensive patients manifest salt-sensitive hypertension. Although the
etiology of salt-sensitive hypertension is undoubtedly multifactorial, there is experimental and
epidemiologic evidence linking abnormalities in the cyclooxygenase (COX)/prostaglandin system to its
pathogenesis. COX-2 inhibitors, as well as non-selective non-steroidal anti-inflammatory drugs (NSAIDs),
are known to elevate blood pressure (BP) and antagonize the BP-lowering effect of antihypertensive
medication in many users. A COX-2 polymorphism that reduces enzymatic activity has been associated
with increased risk of stroke in African Americans. Selective inhibition of COX-2 has been implicated in
increased cardiovascular mortality, which appears to be multifactorial, and may involve increases in BP
and salt and water retention in addition to accelerated thrombogenesis. Therefore, COX-2 activity seems
to be an important mediator of salt and water homeostasis and a guard against development of salt-
sensitive hypertension. The mechanism by which COX inhibition leads to development or exacerbation
of hypertension has been attributed to inhibition of renal COX-2 activity, since salt loading up-regulates
COX-2 expression in the renal medulla, and COX-2 inhibitors reduce urinary sodium excretion. However,
there continues to be controversy about the cellular origins and regulation of the COX-2-derived
prostaglandins that regulate salt and volume homeostasis. Our recently published and preliminary results
provide a novel paradigm to be tested: that COX-2-derived prostaglandins from renal medullary
interstitial cells (RMICs) and renal resident macrophages/dendritic cells work in parallel to
regulate salt and water and blood pressure homeostasis and that abnormalities in either can lead
to development of salt-sensitive hypertension. To test this hypothesis, we propose three specific
aims:
Specific Aim I Investigate the Functional and Structural Roles of COX-2 Expression in Renal
Medullary Interstitial Cells (RMICs)
Specific Aim II Determine Mechanisms by Which Inhibition of Renal Macrophage/Dendritic Cell
COX-2 Expression or Activity Can Potentiate Salt-Sensitive Hypertension
Specific Aim III Determine the Potential Physiologic Role of Renal Macrophages/Dendritic Cells in
Response to Chronic Volume Depletion
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## Key facts

- **NIH application ID:** 9853785
- **Project number:** 5R01DK062794-17
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** RAYMOND C. HARRIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $623,727
- **Award type:** 5
- **Project period:** 2002-12-20 → 2023-01-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853785

## Citation

> US National Institutes of Health, RePORTER application 9853785, The Role of Cyclooxygenase-2 in Salt-Sensitive Hypertension (5R01DK062794-17). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9853785. Licensed CC0.

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