Two-pore domain potassium channels and aldosterone secretion

双孔域钾通道与醛固酮分泌

• 批准号: 9187035
• 负责人: PAULA Q BARRETT
• 金额: $ 43.83万
• 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 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187035
• 关键词: Address; Adrenal Glands; Adrenalectomy; Affect; Agonist; Aldosterone; Angiotensin II; Biological; CYP11B2 gene; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Clinical; Complex Genetic Trait; Data; Defect; Dependence; Depressed mood; Development; Disease; Electrophysiology (science); Essential Hypertension; Evaluation; Excision; Feedback; Functional disorder; Genes; Genetic; Genetic Variation; Genomic approach; Genomics; Goals; Grant; Green Fluorescent Proteins; High Prevalence; Human; Hyperaldosteronism; Hypersensitivity; Hypertension; In Vitro; Investigation; Juxtaglomerular Apparatus; Kidney; Kidney Diseases; Knock-in Mouse; Knockout Mice; Laboratories; Maintenance; Measures; Mediating; Medical; Membrane; Mineralocorticoids; Molecular; Multi-Ethnic Study of Atherosclerosis; Mus; Pathologic; Patients; Phenotype; Plasma; Positioning Attribute; Potassium Channel; Primary Hyperaldosteronism; Production; Proteins; Reagent; Renin; Resistance; Severities; Shapes; Site; Syndrome; Techniques; Testing; Variant; Work; Zona Glomerulosa; blood pressure reduction; calmodulin-dependent protein kinase II; cohort; familial hypertension; genetic analysis; genetic variant; human disease; improved; in vivo; insight; low renin hypertension; mouse model; novel; novel therapeutics; public health relevance; receptor; renin hypertension; response; voltage

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：通常发生低肾素高血压（Lehh）和特发性原发性高醛源性（IHA），并且倾向于心血管和肾脏疾病的发展。在低肾素高血压（LRH）的疾病范围内，高醛溶剂范围从轻度到标记，但始终不适合血浆肾素水平。 LRH的主要原因仍然不确定。在这里，我们提出，过量的醛固酮产生可能不是导致Lehre或IHA中低肾素高血压的唯一因果因素。我们的一般假设是，LRH中低肾素 - 静态状态是对血管紧张素II（ANG II）的敏感性增加的结果，在多个地点表现出来：肾上腺（高醛固酮）脉络膜（高血压）（高血压）（高血压）和/或yxaglomelarular artagtartus Applatus partatus partatus partatus partatus partatus partatus partatus park reback抑制肾素抑制肾素的抑制作用。我们先前证明，编码任务的全球基因两孔结构域钾通道会产生Lehh和Iha的基本特征（低醛固酮高的肾素高血压低：肾素比：ANG II的超敏反应和自主醛酮自治醛固酮产生的可变程度）。因此，我们进一步假设破坏任务通道活动以及去除任务蛋白本身需要产生超反应性 Ang II。为了提供与我们提出的工作相关的人类疾病，我们使用基因组学来测试人类任务通道基因变异的新型关联与高血压，醛固酮，肾素，肾素活性和MESA（动脉粥样硬化的多族裔研究）的衡量，我们建议使用分子/细胞生物学和电子生理学的组合以及验收型技术的组合以及基因级别的培训，以及基因的方法。在AIM 1中，我们生成并验证新的小鼠模型，其中任务通道在产生Zona glomerulosa细胞（ZG）的醛固酮中被删除，其中Task KO ZG细胞由绿色荧光蛋白标记。我们使用这些独特的LRH小鼠模型来确定LRH的哪些表型特征本身是由高醛溶剂产生的。我们使用这些发现来告知人类的遗传分析。在AIM 2中，我们确定了对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； iv）CA通道活性改变了我们的2+拟议的研究将提供有关ZG细胞细胞生物学的新信息，LRH中夸张反应的基础的细胞机制以及任务通道对人类高血压的遗传差异的贡献。如果我们的假设是正确的，它们还将为开发或评估LRH的新医疗治疗提供合理的基础，为此，对当前可用疗法的抵抗力仍然很高。

项目成果

Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells.

• DOI: 10.1161/hypertensionaha.116.08871
• 发表时间: 2017-08
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Yao J;McHedlishvili D;McIntire WE;Guagliardo NA;Erisir A;Coburn CA;Santarelli VP;Bayliss DA;Barrett PQ
• 通讯作者: Barrett PQ