Endothelial Receptor Action in Na-Dependent Hypertension

钠依赖性高血压中内皮受体的作用

• 批准号: 6853172
• 负责人: DAVID M POLLOCK
• 金额: $ 17.65万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853172
• 关键词: NAD(P)H dehydrogenase; angiotensin /renin /aldosterone hypertension; angiotensin II; drug delivery systems; endothelin; enzyme induction /repression; genetically modified animals; hemodynamics; hormone biosynthesis; hormone receptor; interleukin 1; ion transport; kidney function; laboratory mouse; laboratory rat; northern blottings; oxidative stress; receptor expression; renal medulla; statistics /biometry; superoxides; transforming growth factors; ultrasound blood flow measurement; urinalysis; vascular endothelium

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.

项目4的目的是阐明负责内皮素（ET）依赖性血管和肾功能变化的机制，这是由血管紧张素II（ANG II）慢性施用产生的盐依赖性高血压的。 ETA和ETB受体对肾血液动力学和管状功能具有相反的影响，以便降低或增加肾脏消除盐的能力。我们已经表明，通过转化生长因子β（TGFBETA）和白介素1Beta（IL-1Beta），肾脏髓质上皮细胞中的ET产生受到刺激，这在盐负荷过程中肾脏中增加了两个因子。我们假设在盐依赖性高血压中，TGFBETA和/或IL-1BETA刺激肾脏ET的产生，而这又是 通过ETA依赖性超氧化物的产生有助于高血压。超氧化物的过量生产可以抵消NO和其他因素在流体 - 体积调节中的有益作用。我们进一步假设盐依赖性高血压部分是由于缺乏由于氧化应激引起的ETB受体介导的反应。项目4中的第一个目的是检验以下特定假设：TGFBETA和/或IL-1BETA在高盐饮食中刺激高血压大鼠肾脏的ET产生。我们将利用慢性ANG II高血压的大鼠模型来确定肾内TGFBETA，IL-1BETA和ET生产的变化之间的关系。此外，我们预计TGFBETA和/或IL-1BETA敲除小鼠ANG II输注后的ET产生和功能活性较少。 AIM 2将检验以下假设：ETA受体激活刺激大鼠的肾脏依赖盐依赖性高血压的超氧化物的产生。我们的假设预测，ETA受体阻滞将抑制高盐的Ang II高血压大鼠的氧化应激，并且ET的作用是通过体内NADPH氧化酶激活而介导的。 AIM 3将检验以下假设：ETB介导的钠转运抑制在盐依赖性高血压中被超氧化物灭活。我们的假设 预测超氧化物将限制ET减少肾脏内髓质收集管细胞原发性培养物中转运的能力。在体内，我们预计当超氧化物水平升高时，ETB受体激动剂的利尿作用将降低。