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. 项目总结/摘要 低肾素高血压 (LREH) 和特发性原发性醛固酮增多症 (IHA) 常见，并且 容易诱发心血管和肾脏疾病。在低肾素疾病范围内 高血压（LRH）、醛固酮增多症的范围从轻度到显着，但它始终不适合 血浆肾素水平。 LRH 的主要原因仍然不明确。在此，我们建议超额 醛固酮的产生可能不是 LREH 或低肾素高血压的唯一致病因素 伊哈。我们的一般假设是，LRH 中的低肾素高血压状态是肾素高血压增加的结果。 对血管紧张素 II (Ang II) 的敏感性表现在多个部位： 肾上腺（醛固酮增多症） 脉管系统（高血压）和/或肾小球旁装​​置（肾素分泌的反馈抑制，低- 肾素）。我们之前证明编码 TASK 双孔结构域的基因的全局破坏 钾通道产生 LREH 和 IHA（低肾素高血压伴高肾素高血压）的主要特征 醛固酮：肾素比率、对 Ang II 过敏和不同程度的自主醛固酮 生产）。因此，我们进一步假设破坏 TASK 通道活动，以及去除 TASK 蛋白本身需要对 Ang II 产生高反应性。提供人类疾病相关性 我们提出的工作，我们使用基因组学来测试人类 TASK 通道基因变异与 MESA 中高血压、醛固酮、肾素活性和 ARR 的测量（多民族研究） 动脉粥样硬化） 我们建议结合使用分子/细胞生物学和电生理记录技术， 与基因组方法一起，在两个具体目标中检验我们的假设。在目标 1 中，我们生成并 验证新的小鼠模型，其中 TASK 通道在醛固酮产生带中被专门删除 肾小球细胞（ZG），其中 TASK KO ZG 细胞被绿色荧光蛋白标记。我们用这些 独特的 LRH 小鼠模型，以确定 LRH 的哪些表型特征是由 醛固酮增多症本身。我们利用这些发现为人类基因分析提供信息。在目标 2 中，我们 确定对 Ang II 测试贡献超敏的细胞基础： i) TASK 通道活性；二） AT1受体活性状态； iii) 细胞电兴奋性； iv) 改变 Ca 通道活性。我们的 2+ 拟议的研究将提供有关 ZG 细胞生物学的新信息，即 ZG 细胞的细胞机制 LRH 夸大反应的基础，以及 TASK 通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，它们也将为发展或发展提供合理的基础。 LRH 新疗法的评估，该疗法的耐药率仍然很高 目前可用的疗法。