Endothelial Receptor Action in Na-Dependent Hypertension

项目4的目的是阐明慢性应用血管紧张素II(Ang II)引起的盐依赖型高血压患者内皮素(ET)依赖性血管和肾功能改变的机制。ETA和ETB受体对肾脏血流动力学和肾小管功能具有相反的作用，从而分别降低或提高肾脏的排盐能力。我们已经证明，转化生长因子-β(TGFβ)和白介素1-β(IL-1β)刺激肾髓质上皮细胞产生ET，这两个因子在盐负荷时肾脏中会增加。我们假设，在盐依赖型高血压中，TGFβ和/或IL-1β刺激肾脏ET的产生，进而， 通过依赖ETA的超氧化物的产生而导致高血压。超氧化物的过量产生可能会抵消NO和其他在体液容量调节中重要的因素的有益作用。我们进一步假设，盐依赖型高血压在一定程度上是由于氧化应激导致缺乏适当的ETB受体介导的反应。项目4的第一个目标是测试特定的假设，即在给予高盐饮食的高血压大鼠中，转化生长因子β和/或IL-1β刺激高血压大鼠肾脏内ET的产生。我们将利用慢性Ang II高血压大鼠模型来确定肾内转化生长因子β、IL-1β和ET产生的变化之间的关系。此外，我们预计在血管紧张素转换生长因子β和/或IL-1β基因敲除小鼠注射血管紧张素II后，ET的产生和功能活动会减少。目的2验证ETA受体激活刺激盐依赖型高血压大鼠肾脏超氧化物歧化的假说。我们的假设是，阻断ETA受体可抑制Ang II高血压大鼠在高盐环境下的氧化应激，ET的作用是通过体内NADPH氧化酶的激活来实现的。目的3将验证在盐依赖型高血压中ETB介导的钠转运抑制被超氧化物失活的假说。我们的假设 预测超氧化物将限制ET在原代培养的肾内髓集合管细胞中减少转运的能力。在体内，我们预计，当超氧化物水平增加时，ETB受体激动剂在盐依赖型高血压中的利尿作用将会降低。

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.