Regulation of ENaC by Anionic Phospholipids

描述(申请人提供)：高血压是中风和心脏病发作的主要危险因素，几乎每三个美国成年人中就有一个受到影响。一些证据表明，活性氧(ROS)通过作用于心血管系统和肾脏，在盐敏感性高血压中起着非常重要的作用。已知上皮钠通道(ENaC)活性升高可导致高血压。然而，ENaC是否导致盐敏感型高血压仍是完全未知的。因此，了解ROS，特别是细胞内产生的过氧化氢(H_2O_2)在调节ENaC中的作用，将为高血压的治疗提供重要信息。在之前的R01支持下，我们发表了10篇同行评议文章，得出结论：包括磷脂酰肌醇-3，4，5-三磷酸(PI(3，4，5)P3)在内的阴离子磷脂提高了ENaC活性和心尖表达。我们的初步结果表明，由于高盐摄入，远端肾单位细胞中ROS(尤其是H_2O_2)升高，PI(3，4，5)P3升高，并刺激ENaC。目前的提议将通过进行体外和体内实验来检验这一假设。第一个具体目标是确定ROS刺激ENaC的机制。第二个具体目的是确定高盐摄入量是否通过提高盐敏感大鼠远端肾单位细胞中的ROS来矛盾地刺激ENaC。这些研究应该为盐敏感型高血压的发病机制提供更多的信息。 与公共健康相关：几乎每三个美国成年人中就有一个患有高血压。目前的建议将使用培养的细胞和盐敏感的大鼠模型来确定高盐饮食如何导致高血压。这项研究将重点放在肾脏上皮钠通道和活性氧的作用上。

DESCRIPTION (provided by applicant): Hypertension, which is a major risk factor for stroke and heart attack, affects nearly one out of every three US adults. Several lines of evidence suggest that reactive oxygen species (ROS) plays a very important role in the salt-sensitive hypertension, by targeting both cardiovascular system and the kidney. It is known that elevated activity of the epithelial sodium channel (ENaC) can lead to hypertension. However, whether ENaC contributes to salt-sensitive hypertension remains completely unknown. Therefore, understanding the role of ROS, especially hydrogen peroxide (H2O2) produced in the cell, in regulating ENaC should provide important information for the treatment of hypertension. With the previous R01 support, we have published 10 peer- reviewed articles and concluded that anionic phospholipids including phophatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) elevates ENaC activity and apical expression. Our preliminary results suggest a hypothesis that ROS (particularly H2O2) is elevated in the distal nephron cells due to high salt intake, elevates PI(3,4,5)P3, and stimulates ENaC. The present proposal will test this hypothesis by performing both in vitro and in vivo experiments. The first specific aim is to determine the mechanism by which ROS stimulates ENaC. The second specific aim is to determine whether the mechanism by which high salt intake paradoxically stimulates ENaC by elevating ROS in the distal nephron cells of salt-sensitive rats. These studies should provide additional information for the pathogenesis of salt-sensitive hypertension PUBLIC HEALTH RELEVANCE: Hypertension affects nearly one out of every three US adults. The present proposal will use both cultured cells and a salt-sensitive rat model to determine how high salt diet causes hypertension. The study will focus on the role of the epithelial sodium channel and reactive oxygen species in the kidney.