The objective of Project 4 is to elucidate mechanisms responsible for changes in endothelin (ET)-dependent vascular and renal function in salt-dependent hypertension produced by chronic administration of angiotensin II (Ang II). ETA and ETB receptors have opposing effects on renal hemodynamics and tubular function so as to decrease or increase the kidney's ability to eliminate salt, respectively. We have shown that ET production in renal medullary epithelial cells is stimulated by transforming growth factor-Beta (TGFbeta) and interleukin-1Beta (IL-1beta), two factors that are increased in the kidneys during salt loading. We hypothesize that in salt-dependent hypertension, TGFbeta and/or IL-1beta stimulate renal ET production, that in turn, contributes to hypertension via ETA-dependent superoxide production. Overproduction of superoxide can negate the beneficial actions of NO and other factors important in fluid-volume regulation. We further hypothesize that salt-dependent hypertension is due, in part, to the lack of appropriate ETB receptor mediated responses due to oxidative stress.
The first aim i n Project 4 is to test the specific hypothesis that TGFbeta and/or IL-1beta stimulate ET production in the kidney of hypertensive rats given a high salt diet. We will utilize a rat model of chronic Ang II hypertension to determine the relationship between changes in intrarenal TGFbeta, IL-1beta, and ET production. In addition, we expect less ET production and functional activity following Ang II infusion in TGFbeta and/or IL-1beta knock-out mice.
Aim 2 will test the hypothesis that ETA receptor activation stimulates superoxide production in the kidney of rats with salt-dependent hypertension. Our hypothesis predicts that ETA receptor blockade will inhibit oxidative stress in Ang II hypertensive rats on high salt, and that the effects of ET are mediated by activation of NADPH oxidase in vivo.
Aim 3 will test the hypothesis that ETB-mediated inhibition of sodium transport is inactivated by superoxide in salt-dependent hypertension. Our hypothesis predicts that superoxide will limit the ability of ET to decrease transport in primary cultures of renal inner medullary collecting duct cells. In vivo, we expect that the diuretic effects of ETB receptor agonists will be reduced in salt-dependent hypertension when superoxide levels are increased.
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