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

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）：血压部分通过远端肾单位调节钠重吸收来控制。在这里，上皮钠通道 (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，它会增加 ENaC 活性，从而升高血压。人类通过经典的负反馈机制控制血压，随着血压下降，RAAS 会激活 ENaC。所有形式的遗传性单基因高血压都与盐敏感性有关，是由于血压升高时 ENaC 的不适当激活所致。这些严重但罕见的高血压疾病是由 ENaC 或其上游调节因子 RAAS 的功能突变引起的。更常见但不太严重的原发性高血压是多基因高血压倾向的表现，生活方式选择和环境因素会加剧这种倾向。许多原发性高血压，尤其是非洲裔美国人的原发性高血压，与盐敏感性以及低肾素和醛固酮水平有关。由于负反馈调节，盐敏感性高血压、低肾素和醛固酮与 ENaC 功能障碍有关。分子遗传学研究发现非洲裔美国人群体中丰富的 ENaC 序列变异（多态性）。最近有人提出，非裔美国人人群中普遍存在的四种 ENaC 多态性（αT334A、C618F、T663A 和 β T594M）与低肾素/醛固酮高血压之间可能存在联系；然而，这些多态性对 ENaC 功能的影响仍有待测试。因此，尚不清楚这些多态性是否在某些形式的盐敏感性高血压中发挥致病作用。当前的提案通过测试 ENaC 多态性增加通道活动的假设来解决这个问题。我们的实验室有能力进行这项研究，因为我们能够评估重组 ENaC 在哺乳动物表达系统中的功能。我们将利用这些专业知识来实现​​两个具体目标：1) 确定 ENaC 多态性对通道活动的影响； 2) 确定多态性 ENaC 增加活性的细胞/分子机制。初步结果支持了这项调查的可行性，并表明这一调查路线将产生重要且新颖的发现。