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.
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.
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