Renal control of sodium excretion is of obvious importance in determining salt-sensitivity and blood pressure. High blood pressure related to impaired pressure natriuresis is evident in a nnajority of human subjects and a primary consequence of this disorder is vascular dysfunction and end-organ damage. Animal studies have established that ETA receptors cause hypertension in saltdependent models. In contrast, ETB receptors function in the opposite manner by promoting salt and water excretion as well as stimulating vascular relaxation. However, ETB receptor function is complicated due to their presence on nerves and vascular smooth muscle, which can produce vasoconstriction under some circumstances. Furthermore, we have recently reported that female, but not male, rats have an ETA-dependent natriuretic pathway similar to that of the ETB receptor. Therefore, the discernment of receptor-specific mechanisms for the control of renal hemodynamic and excretory function by ET-1 requires clarification. The current project is based on our recent observations that ETA receptor blockade reduces renal Inflammation, and considerable evidence that a lack of ETB receptor function results in salt-sensitive hypertension. Our proposal will first address the hypothesis that the ETA receptor is an important pro-inflammatory mechanism in the kidney and that the ETB receptor normally functions to protect against these changes. We further propose that the ETB receptor is unable to fully compensate for increased ET-1 activity in salt-dependent hypertension due to an impaired ability of renal medullary ETB receptors to promote sodium excretion. The proposed studies will determine the role of Inflammation and oxidative stress in rat models that are associated with increased ET-1 activation.
Aim 1. Test the hypothesis that ET-1, via the ETA receptor, directly stimulates inflammation, oxidative stress, and increases in glomerular permeability in the kidney - actions that are opposed by ETB receptor activation.
Aim 2. Test the hypothesis that ETB dependent control of blood pressure, microcirculatory function, and natriuresis is attenuated in Ang ll-dependent hypertension.
Aim 3. Test the hypothesis that female rats are protected against salt- sensitive hypertension by the existence of an ETA-dependent natriuretic mechanism.

Public Health Relevance

This project focuses on elucidating mechanisms by which the kidney controls sodium excretion, and therefore, has direct relevance to the serious health problem of salt-dependent hypertension and kidney disease. These studies also will provide new information related to the process of developing chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
7P01HL095499-05
Application #
8661221
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-08-05
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
$298,353
Indirect Cost
$93,346
Name
University of Alabama Birmingham
Department
Type
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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