Two-pore domain potassium channels and aldosterone secretion

双孔域钾通道与醛固酮分泌

• 批准号: 8629854
• 负责人: PAULA Q BARRETT
• 金额: $ 43.08万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-03 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629854
• 关键词: Address; Adrenal Glands; Adrenalectomy; Affect; Agonist; Aldosterone; Aldosterone Synthase; Angiotensin II; Atherosclerosis; Back; Bilateral; Biological; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Clinical; Complex Genetic Trait; Data; Defect; Dependence; Depressed mood; Development; Disease; Essential Hypertension; Evaluation; Excision; Feedback; Functional disorder; Genes; Genetic; Genetic Variation; Genomics; Goals; Grant; Green Fluorescent Proteins; High Prevalence; Human; Hyperaldosteronism; Hypersensitivity; Hypertension; In Vitro; Juxtaglomerular Apparatus; Kidney; Kidney Diseases; Knock-in Mouse; Laboratories; Maintenance; Measures; Mediating; Medical; Membrane; Mineralocorticoids; Molecular; Mus; Patients; Plasma; Positioning Attribute; Potassium Channel; Primary Hyperaldosteronism; Production; Proteins; Reagent; Renin; Resistance; Severities; Shapes; Site; Syndrome; Techniques; Testing; Variant; Work; Zona Glomerulosa; aldosterone hypertension; base; calmodulin-dependent protein kinase II; cohort; familial hypertension; feeding; genetic analysis; genetic variant; human disease; improved; in vivo; insight; low renin hypertension; mouse model; novel; public health relevance; receptor; renin hypertension; response; voltage

7. Project Summary / Abstract Low-renin hypertension (LREH) and idiopathic primary hyperaldosteronism (IHA) occur commonly, and predispose to the development of cardiovascular and renal disease. Within the disease spectrum of low renin hypertension (LRH), hyperaldosteronism ranges from mild to marked, but it always remains inappropriate for the level of plasma renin. The primary causes for LRH remain ill-defined. Here, we propose that excess aldosterone production may not be the sole causative factor contributing to low-renin hypertension in LREH or IHA. Our general hypothesis is that the low renin-hypertensive state in LRH is a consequence of an increased sensitivity to Angiotensin II (Ang II) manifest at multiple sites: the adrenal gland (hyperaldosteronism) the vasculature (hypertension) and/or the juxtaglomerular apparatus (feed-back inhibition of renin secretion, low- renin). We previously demonstrated that global disruption of genes encoding TASK two-pore domain potassium channels produces cardinal features of LREH and IHA (low renin hypertension with high aldosterone:renin ratios, hypersensitivity to Ang II and variable degrees of autonomous aldosterone production). Therefore, we further hypothesize that disrupting TASK channel activity, as well as the removal of TASK protein itself, is required to produce hyper-reactivity to Ang II. To provide human disease relevance to our proposed work, we use genomics to test for novel associations of human TASK channel gene variants with measures of hypertension, aldosterone, renin activity and ARR in MESA (Multi-Ethnic Study of Atherosclerosis) We propose to use a combination of molecular/cell biological and electrophysiological recording techniques, along with genomic approaches, to test our hypotheses in two Specific Aims. In Aim 1, we generate and validate new mouse models in which TASK channels are deleted specifically in aldosterone producing zona glomerulosa cells (ZG) and in which TASK KO ZG cells are marked by green fluorescent protein. We use these unique mouse models of LRH to determine which phenotypic features of LRH are produced by hyperaldosteronism, per se. We use these findings to inform a genetic analysis in humans. In Aim 2, we determine the cellular basis for hypersensitivity to Ang II testing contributions of: i) TASK channel activity; ii) AT1 receptor activity-state; iii) cellular electrical excitability; and iv) altered Ca channel activity. Our 2+ proposed studies will provide new information about the cell biology of ZG cells, the cellular mechanisms that underlie exaggerated responses in LRH, and the contribution of genetic differences in TASK channels to human hypertension. If our hypotheses are correct, they also will provide a rational basis for development or evaluation of new medical treatments for LRH, for which there remains a high prevalence of resistance to currently available therapies.

7。项目摘要 /摘要 低肾素高血压（Leh）和特发性原发性高醛源性（IHA）通常发生，并且 易感心血管和肾脏疾病的发展。在低肾素的疾病频谱中 高血压（LRH），催眠醛固酮含量从轻度到标记不等，但始终不适合 血浆肾素的水平。 LRH的主要原因仍然不确定。在这里，我们提出了多余的 醛固酮的产量可能不是唯一导致l鼠中低肾素高血压的唯一因果因素 iha。我们的总体假设是，LRH中低的肾素 - 静态状态是增加的结果 对血管紧张素II（ANG II）的敏感性在多个部位表现出 脉管系统（高血压）和/或近齿状设备（对肾素分泌的饲料抑制作用，低 - 肾素）。我们以前证明了编码任务的全球基因两孔域的破坏 钾通道可产生Leh和Iha的基本特征（低肾素高血压高 醛固酮：肾素比，对ANG II的超敏反应和自主醛固酮的可变程度 生产）。因此，我们进一步假设破坏任务渠道活动以及删除 任务蛋白本身是需要对ANG II产生过度反应性的。提供与人类疾病相关的 我们提出的工作，我们使用基因组学来测试人类任务渠道基因变体的新型关联 高血压，醛固酮，肾素活性和ARR的度量（多种族研究 动脉粥样硬化） 我们建议使用分子/细胞生物学和电生理记录技术的组合， 与基因组方法一起，以两个具体目标来检验我们的假设。在AIM 1中，我们产生并 验证新鼠标模型，其中任务通道在醛固酮中专门删除，产生Zona 肾小球细胞（ZG）和任务KO ZG细胞以绿色荧光蛋白为标志。我们使用这些 LRH的独特小鼠模型，以确定LRH的哪些表型特征由 催眠醛酸，本身。我们使用这些发现来告知人类的遗传分析。在AIM 2中，我们 确定对ANG II测试贡献过敏的细胞基础：i）任务通道活动； ii） AT1受体活动状态； iii）细胞电兴奋性；和iv）改变了CA通道活性。我们的 2+ 拟议的研究将提供有关ZG细胞细胞生物学的新信息，ZG细胞是细胞机制 LRH中夸张的反应是基础的，以及任务渠道中遗传差异的贡献 人类高血压。如果我们的假设是正确的，它们还将为开发或 评估LRH的新医疗治疗，对此仍存在很高的抵抗力 目前可用的疗法。