Regulation of ENaC by Anionic Phospholipids

描述（由申请人提供）：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。大量证据表明活性氧（reactive oxygen species，ROS）通过靶向心血管系统和肾脏在盐敏感性高血压中发挥重要作用。已知上皮钠通道（ENaC）的活性升高可导致高血压。然而，ENaC是否有助于盐敏感性高血压仍然完全未知。因此，了解细胞内产生的ROS，特别是过氧化氢（H2 O2）在调节ENaC中的作用，将为高血压的治疗提供重要信息。在先前的R 01支持下，我们已经发表了10篇同行评审文章，并得出结论，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活性和顶端表达。我们的初步研究结果表明，ROS（特别是H2 O2）是由于高盐摄入量的远端肾单位细胞升高，提高PI（3，4，5）P3，并刺激ENaC的假设。本提案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。第二个具体目标是确定高盐摄入的机制是否矛盾地通过升高盐敏感大鼠远端肾单位细胞中的ROS来刺激ENaC。这些研究将为盐敏感性高血压的发病机制提供更多的信息 公共卫生相关性：高血压影响近三分之一的美国成年人。目前的提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。这项研究将集中在上皮钠通道和活性氧在肾脏中的作用。

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.