Endothelial Receptor Action in Na-Dependent Hypertension

项目4的目的是阐明血管紧张素II（Ang II）慢性给药引起的盐依赖性高血压中内皮素（ET）依赖性血管和肾功能变化的机制。ETA和ETB受体对肾血流动力学和肾小管功能具有相反的作用，从而分别降低或增加肾脏排盐的能力。我们已经表明，肾髓质上皮细胞中的ET产生受到转化生长因子β（TGF β）和白细胞介素-1 β（IL-1 β）的刺激，这两种因子在盐负荷期间在肾脏中增加。我们假设在盐依赖性高血压中，TGF β和/或IL-1 β刺激肾脏ET的产生，反过来， 通过ETA依赖性超氧化物产生导致高血压。超氧化物的过量产生可以否定NO和其他在液体容量调节中重要的因素的有益作用。我们进一步假设盐依赖性高血压部分是由于氧化应激导致的ETB受体介导的反应缺乏。项目4的第一个目的是检验TGF β和/或IL-1 β刺激高盐饮食高血压大鼠肾脏ET产生的特定假设。我们将利用慢性血管紧张素II高血压大鼠模型，以确定肾内TGF β，IL-1 β和ET产生的变化之间的关系。此外，我们预计在TGF β和/或IL-1 β敲除小鼠中输注Ang II后，ET产生和功能活动减少。目的2：验证盐依赖性高血压大鼠肾脏ETA受体激活刺激超氧化物生成的假说。我们的假设是，阻断ETA受体可抑制高盐条件下Ang II高血压大鼠的氧化应激，并且ET的作用是通过激活NADPH氧化酶介导的。目的3将检验在盐依赖性高血压中ETB介导的钠转运抑制被超氧化物灭活的假设。我们的假设 预测超氧化物将限制ET降低肾内髓集合管细胞原代培养物转运的能力。在体内，我们预期当超氧化物水平增加时，ETB受体激动剂的利尿作用将在盐依赖性高血压中降低。

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 in 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.