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 !

Public Health Relevance

The proposed studies will investigate the roles of prostaglandins derived from cyclooxygenase-2 (COX-2) in regulation of salt and water homeostasis by the kidney and will investigate how inhibition of COX-2 can potentiate salt-sensitive hypertension. The overriding hypothesis to be tested is that expression of COX-2 in medullary interstitial cells intrinsic to the kidney and in renal resident macrophage/dendritic cells together mediate prostaglandin-mediated regulation of salt and water by the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK062794-16A1
Application #
9660786
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mullins, Christopher V
Project Start
2002-12-20
Project End
2023-01-01
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
16
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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