Regulation of ENaC by Anionic Phospholipids

阴离子磷脂对 ENaC 的调节

• 批准号: 8319541
• 负责人: HE-PING MA
• 金额: $ 23.02万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8319541
• 关键词: 5' -AMP-activated protein kinase; Address; Adult; Affect; Animals; Apical; Cardiovascular system; Cells; Cultured Cells; Data; Diet; Distal; Duct (organ) structure; Epithelial; Feedback; Funding; Generations; Goals; Health; Hydrogen Peroxide; Hypertension; In Vitro; Ion Channel; Kidney; Laboratories; Lead; Mediating; Membrane Lipids; Membrane Potentials; Modeling; Myocardial Infarction; NADPH Oxidase; Natriuresis; Nephrons; Oxidative Stress; Pathogenesis; Peer Review; Phospholipids; Play; Probability; Publishing; Rattus; Reactive Oxygen Species; Regulation; Resistance; Risk Factors; Role; Series; Sgk protein; Signal Transduction Pathway; Sodium; Sodium Channel; Sodium Chloride; Stroke; Testing; Work; apical membrane; blood pressure regulation; catalase; driving force; epithelial Na+ channel; extracellular; hypertension treatment; in vivo; interstitial; kidney cortex; novel; phosphoinositide-3,4,5-triphosphate; research study; salt intake; salt sensitive; ubiquitin ligase

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.

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，影响了美国三个成年人中的几乎一个。几条证据表明，通过靶向心血管系统和肾脏，活性氧（ROS）在盐敏感的高血压中起着非常重要的作用。众所周知，上皮钠通道（ENAC）的活性升高会导致高血压。但是，ENAC是否有助于盐敏感的高血压仍然完全未知。因此，了解细胞中产生的ROS，尤其是过氧化氢（H2O2）在调节ENAC中的作用，应提供重要信息以治疗高血压。在先前的R01支持下，我们发表了10份同行评审的文章，并得出结论，包括磷脂酰肌醇在内的阴离子磷脂-3,4,5-三磷酸（PI（3,4,5）P3）升高了eNAC活性和基本表达。我们的初步结果表明，由于高盐的摄入量，远端肾单位细胞中ROS（尤其是H2O2）升高，升高Pi（3,4,5）P3并刺激ENAC。本建议将通过进行体外和体内实验来检验这一假设。第一个具体目的是确定ROS刺激ENAC的机制。第二个具体目的是确定高盐摄入量矛盾的机制是否通过升高盐敏感大鼠远端肾单位细胞中的ROS来刺激ENAC。这些研究应为盐敏感高血压发病机理提供其他信息 公共卫生相关性：高血压影响每三分之一的成年人中有近一个。本提案将同时使用培养的细胞和盐敏感大鼠模型来确定高盐饮食如何引起高血压。该研究将重点介绍上皮钠通道和肾脏中的活性氧的作用。

项目成果

Fulvene-5 inhibition of Nadph oxidases attenuates activation of epithelial sodium channels in A6 distal nephron cells.

Fulvene-5 抑制 Nadph 氧化酶会减弱 A6 远端肾单位细胞上皮钠通道的激活。

• DOI: 10.1152/ajprenal.00098.2013
• 发表时间: 2013
• 期刊: American journal of physiology. Renal physiology
• 作者: Trac,David;Liu,Bingchen;Pao,AlanC;Thomas,SheelaV;Park,Michael;Downs,CharlesA;Ma,He-Ping;Helms,MyN
• 通讯作者: Helms,MyN

Acidic ATP activates lymphocyte outwardly rectifying chloride channels via a novel pathway.

酸性 ATP 通过一种新途径激活淋巴细胞向外调整氯离子通道。

• DOI: 10.1007/s00424-004-1305-2
• 发表时间: 2004
• 期刊: Pflugers Archiv : European journal of physiology
• 作者: Ma,He-Ping;Zhou,Zhen-Hong;Liang,You-You;Saxena,Sunil;Warnock,DavidG
• 通讯作者: Warnock,DavidG

Anionic phospholipids differentially regulate the epithelial sodium channel (ENaC) by interacting with alpha, beta, and gamma ENaC subunits.

• DOI: 10.1007/s00424-009-0733-4
• 发表时间: 2010-02
• 期刊: PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
• 影响因子: 4.5
• 作者: Zhang, Zhi-Ren;Chou, Chu-Fang;Wang, Jing;Liang, You-You;Ma, He-Ping
• 通讯作者: Ma, He-Ping

Lovastatin inhibits human B lymphoma cell proliferation by reducing intracellular ROS and TRPC6 expression.

• DOI: 10.1016/j.bbamcr.2014.02.002
• 发表时间: 2014-05
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
• 影响因子: 5.1
• 作者: Song, Xiang;Liu, Bing-Chen;Lu, Xiao-Yu;Yang, Li-Li;Zhai, Yu-Jia;Eaton, Amity F.;Thai, Tiffany L.;Eaton, Douglas C.;Ma, He-Ping;Shen, Bao-Zhong
• 通讯作者: Shen, Bao-Zhong

Hydrogen sulfide prevents hydrogen peroxide-induced activation of epithelial sodium channel through a PTEN/PI(3,4,5)P3 dependent pathway.

• DOI: 10.1371/journal.pone.0064304
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhang J;Chen S;Liu H;Zhang B;Zhao Y;Ma K;Zhao D;Wang Q;Ma H;Zhang Z
• 通讯作者: Zhang Z