Two-pore domain potassium channels and aldosterone secretion

双孔域钾通道与醛固酮分泌

• 批准号: 8786092
• 负责人: PAULA Q BARRETT
• 金额: $ 43.17万
• 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/8786092
• 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; Genomic approach; Genomics; Goals; Grant; Green Fluorescent Proteins; Health; 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; blood pressure reduction; 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; 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）：低肾素高血压（LREH）和特发性原发性醛固酮增多症（IHA）常见，并且容易发生心血管和肾脏疾病。在低肾素高血压 (LRH) 疾病谱中，醛固酮增多症的范围从轻度到显着，但始终不适合血浆肾素水平。 LRH 的主要原因仍然不明确。在这里，我们提出醛固酮生成过多可能不是导致 LREH 或 IHA 低肾素高血压的唯一致病因素。我们的一般假设是，LRH 的低肾素高血压状态是由于多个部位对血管紧张素 II (Ang II) 的敏感性增加所致：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 双孔结构域钾通道的基因的整体破坏会产生 LREH 和 IHA 的主要特征（低肾素高血压，高醛固酮：肾素比率，对 Ang II 过敏和不同程度的自主醛固酮产生）。因此，我们进一步假设，破坏 TASK 通道活性以及去除 TASK 蛋白本身是产生高反应性所必需的。 安二世。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 TASK 通道基因变异与 MESA（动脉粥样硬化多种族研究）中高血压、醛固酮、肾素活性和 ARR 的测量的新关联。结合分子/细胞生物学和电生理学记录技术以及基因组方法，以测试我们在两个特定目标中的假设。在目标 1 中，我们生成并验证了新的小鼠模型，其中在产生醛固酮的球状带细胞 (ZG) 中专门删除了 TASK 通道，并且其中 TASK KO ZG 细胞被绿色荧光蛋白标记。我们使用这些独特的 LRH 小鼠模型来确定 LRH 的哪些表型特征是由醛固酮增多症本身产生的。我们利用这些发现为人类基因分析提供信息。在目标 2 中，我们确定了对 Ang II 测试贡献超敏的细胞基础： i) TASK 通道活性； ii) AT1受体活性状态； iii) 细胞电兴奋性； iv) 改变 Ca 通道活性 我们提出的 2+ 项研究将提供有关 ZG 细胞的细胞生物学、LRH 过度反应的细胞机制以及 TASK 通道遗传差异对人类高血压的影响的新信息。如果我们的假设是正确的，它们也将为开发或评估 LRH 新的医学治疗方法提供合理的基础，目前 LRH 疗法的耐药率仍然很高。