Epithelial Na channel (ENaC) polymorphisms in hyptertention

高血压中的上皮钠通道 (ENaC) 多态性

• 批准号: 7010908
• 负责人: James D Stockand
• 金额: $ 14.6万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010908
• 关键词: African American; CHO cells; angiotensin /renin /aldosterone hypertension; clinical research; environmental exposure; genetic polymorphism; human genetic material tag; hypertension; membrane permeability; molecular dynamics; molecular genetics; renin angiotensin system; sodium channel; transfection; voltage /patch clamp; African American; CHO cells; angiotensin /renin /aldosterone hypertension; clinical research; environmental exposure; genetic polymorphism; human genetic material tag; hypertension; membrane permeability; molecular dynamics; molecular genetics; renin angiotensin system; sodium channel; transfection; voltage /patch clamp

DESCRIPTION (provided by applicant): Blood pressure is controlled, in part, by regulated sodium reabsorption at the distal renal nephron. Here, activity of the epithelial Na channel (ENaC) is limiting for sodium reabsorption. Aldosterone, the final hormone in the renin-angiotensin-aldosterone-system (RAAS), increases ENaC activity to increase blood pressure. Humans control blood pressure through a classic negative-feedback mechanism with RAAS activating ENaC as blood pressure falls. All forms of inheritable, monogenic hypertension are associated with salt-sensitivity and result from inappropriate activation of ENaC in the face of elevated blood pressure. These severe but rare hypertensive diseases result from either gain of function mutations in ENaC or its upstream regulator RAAS. The more prevalent but less severe essential hypertension is a manifestation of a polygenic predisposition towards elevated blood pressure exacerbated by life-style choices and environmental factors. Much essential hypertension particularly that in African American populations is associated with salt-sensitivity and low renin and aldosterone levels. Due to negative-feedback regulation, hypertension with salt-sensitivity, low renin and aldosterone implicates ENaC dysfunction. Molecular genetic studies identified sequence variations (polymorphisms) in ENaC enriched in African American populations. Possible linkage between four ENaC polymorphisms prevalent in African American populations, (alphaT334A, C618F, T663A and beta T594M) with low-renin/aldosterone hypertension has recently been suggested; however, the effects of these polymorphisms on ENaC function remain to be tested. Thus, it is unclear if these polymorphisms can play a causative role in some forms of salt-sensitive hypertension. The current proposal addresses this question by testing the hypothesis that ENaC polymorphisms increase channel activity. Our laboratory is well positioned to conduct this investigation for we are capable of assessing function of recombinant ENaC in a mammalian expression system. We will utilize this expertise to address two Specific Aims: 1) Determine the effects of ENaC polymorphisms on channel activity; and 2) Determine the cellular/molecular mechanisms by which polymorphic ENaC has increased activity. Preliminary results support the feasibility of this investigation and suggest that this line of inquiry will yield significant and novel findings.

描述（由申请人提供）：血压由远端肾脏肾单位的调节钠重吸收来部分控制。在这里，上皮Na通道（ENAC）的活性限制了钠的重吸收。醛固酮是肾素 - 血管紧张素 - 醛固酮系统（RAAS）中的最终激素，增加了ENAC活性以增加血压。人类通过经典的负反馈机制控制血压，随着血压下降，RAAS激活ENAC。所有形式的遗传性，单基因高血压都与盐的敏感性有关，并且由于血压升高而导致ENAC的激活不当。这些严重但罕见的高血压疾病是由于ENAC中的功能突变或其上游调节剂RAA的增益而引起的。越普遍但不太严重的基本高血压是一种多基因易感性的体现，其血压升高会因生活方式的选择和环境因素加剧。特别是重要的高血压，特别是在非裔美国人中，盐的敏感性和低肾素和醛固酮水平与盐的敏感性低有关。由于反馈的负调节，盐敏感的高血压，低肾素和醛固酮与ENAC功能障碍有关。分子遗传研究确定了富含非裔美国人种群的ENAC中的序列变化（多态性）。最近已经提出，在非洲裔美国人口中普遍存在的四种ENAC多态性（Alphat334a，C618F，T663A和Beta T594M）与低肾/醛固酮/醛固酮高血压之间可能存在联系。但是，这些多态性对ENAC功能的影响仍有待测试。因此，目前尚不清楚这些多态性是否可以在某些形式的盐敏感性高血压中起因果作用。当前的提案通过检验ENAC多态性增加通道活性的假设来解决这个问题。我们的实验室在进行这项研究方面有好处，因为我们能够评估重组ENAC在哺乳动物表达系统中的功能。我们将利用此专业知识来解决两个具体目标：1）确定ENAC多态性对信道活动的影响； 2）确定多态性ENAC具有增加活性的细胞/分子机制。初步结果支持这项研究的可行性，并表明这种询问线将产生重大和新颖的发现。