Salt-sensitive hypertension: Role of renal superoxide

描述（由申请人提供）：盐敏感性高血压是美国常见的高血压之一。盐敏感性高血压的病理主要是由于肾脏不能排泄盐。促进肾盐和水潴留的因素和有利于排泄的因素之间存在平衡。本项目重点研究了一个有利于盐和水保持的因素——超氧化物（02-）。最近的证据表明，盐敏感性高血压可能是肾脏02-生成增强的结果。据报道，在达尔盐敏感大鼠中，Henle环的增厚升肢是增加盐潴留的原因，但02-对增厚升肢运输的影响尚不清楚。已证明02-直接影响非肾组织的转运，并通过清除NO增加血管反应性和小管肾小球反馈。然而，很少有研究直接探讨02-改变尿量或钠排泄的机制，基本上没有研究探讨活性氧如何增强肾元各节段的净NaCl吸收。我们假设盐敏感性高血压至少部分是由于厚升肢中02水平升高导致不适当的盐和水潴留。02-通过产生激活蛋白激酶C的异前列腺素和减弱一氧化氮（NO）的抑制作用来刺激这一段的运输。在Aim I中，我们将研究内源性02-对粗升肢净NaC1吸收的影响，并确定受影响的转运蛋白。在Aim II中，我们将研究由02-激活的第二信使级联。在Aim III中，我们将研究NO和02之间的相互作用，以确定粗升肢对盐的吸收。在Aim IV中，我们将研究高盐饮食对02-生成的影响，以及饮食中的含盐量是否会改变02-改变肾功能的能力。在Aim V中，我们将研究02-对达尔大鼠盐敏感性高血压的贡献，并阐明02-产生或分解代谢的变化如何改变尿量和钠排泄。该项目将为02-调控盐吸收及其在盐敏感性高血压中的作用提供重要的新信息。

DESCRIPTION (provided by applicant): Salt-sensitive hypertension is one of the prevalent forms of high blood pressure in the United States. The pathology of salt-sensitive hypertension is due primarily to an inability of the kidney to excrete salt. A balance exists between factors promoting renal salt and water retention and those favoring excretion. This project focuses on one factor favoring salt and water retention, superoxide (02-). Recent evidence shows that salt-sensitive hypertension may be a result of enhanced 02- production by the kidney. The thick ascending limb of the loop of Henle has been reported to be responsible for augmented salt retention in the Dahl salt-sensitive rat, but the effects of 02- on thick ascending limb transport are unknown. 02- has been shown to affect transport directly in non-renal tissue and to increase vascular reactivity and tubuloglomerular feedback by scavenging NO. However, there have been very few studies directly addressing the mechanism by which 02- alters urinary volume or sodium excretion, and essentially no studies addressing how reactive oxygen species may enhance net NaCl absorption by the various nephron segments. We hypothesize that salt-sensitive hypertension is at least in part due to elevated 02- levels in the thick ascending limb which cause inappropriate salt and water retention. 02- stimulates transport in this segment by generating isoprostanes that activate protein kinase C and by blunting the inhibitory effect of nitric oxide (NO). In Aim I we will study the effects of endogenously produced 02- on net NaC1 absorption by thick ascending limbs and identify the transporter(s) affected. In Aim II we will study the second messenger cascade activated by 02-. In Aim III we will study the interaction between NO and 02-in determining salt absorption by the thick ascending limb. In Aim IV we will study the effects of a high-salt diet on 02- production, and whether the salt content of the diet alters the ability of 02- to change renal function. In Aim V we will study the contribution of 02- to salt-sensitive hypertension in the Dahl rat and clarify how changes in 02- production or catabolism alter urinary volume and sodium excretion. This project will provide important new information concerning the regulation of salt absorption by 02- and its role in salt-sensitive hypertension.