Analysis of distal conboluted tubule function in vivo

体内远端复合小管功能分析

• 批准号: 7384241
• 负责人: JAMES A MCCORMICK
• 金额: $ 12.54万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384241
• 关键词: Accounting; Adult; Affect; Aldosterone; Alkalosis; Animals; Apical; Blood; Blood Pressure; Breeding; Cessation of life; Chronic Kidney Failure; Clinical; Complement; Condition; Congestive Heart Failure; Defect; Development; Diet; Dietary Sodium; Disease; Disruption; Distal; Distal convoluted renal tubule structure; Electrolytes; Enterobacteria phage P1 Cre recombinase; Essential Hypertension; Extracellular Fluid; Future; Generations; Genes; Goals; Hormones; Hypertension; Hypokalemia; Hypotension; Ion Channel; Ion Transport; Kidney; Maintenance; Measurement; Measures; Mediating; Mentors; Metabolic; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Mus; Mutation; Myocardial Infarction; Na(+)-K(+)-Exchanging ATPase; Nephrology; Nucleic Acid Regulatory Sequences; Numbers; Pathogenesis; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Plasma; Play; Population; Potassium; Protein Overexpression; Proteomics; Pseudohypoaldosteronism; Receptor Gene; Regulation; Research; Risk Factors; Role; Site; Sodium; Sodium Chloride; Stroke; Structure; Symptoms; Syndrome; System; Tamoxifen; Therapeutic; Thiazide Diuretics; Transgenes; Transgenic Mice; Type II Pseudohypoaldosteronism; United States; Western Blotting; basolateral membrane; blood pressure regulation; career; in vivo; inhibitor/antagonist; insight; mouse model; programs; promoter; sodium-chloride cotransporter; symporter; thiazide; urinary

DESCRIPTION (provided by applicant): Hypertension affects approximately 25% of the adult population in the United States and is an important risk factor for death from stroke, myocardial infarction, congestive heart failure, and chronic kidney disease. The distal convoluted tubule (DCT) of the kidney plays a critical role in the reabsorption of sodium (primarily via the sodium chloride cotransporter, NCC) and hence in regulation of blood pressure. This is best illustrated by the disease Pseudohypoaldosteronism type II (PHAII), characterized by hyperkalemic hypertension, caused by gene defects in regulators of NCC that enhance its activity. PHAII is remediable by treatment with thiazide diuretics, which specifically inhibit NCC. Importantly, thiazide diuretics are the first therapuetic choice in the majority of hypertensive patients, not just those with PHAII. There is controversy as to whether PHAII is caused solely by altered NCC activity, or whether dysregulation of other ion channels and transporters is involved. There is also evidence that NCC activity is regulated by the mineralocorticoid hormone aldosterone. Since levels of the mineralocorticoid receptor are low in the DCT, the physiological effects of aldosterone on this kidney segment are unclear. This proposal aims to characterize two mouse models to give better insight into PHAII and DCT function. (1) Generation and analysis of mice over-expressing NCC in the DCT, as a possible model of PHAII. Blood pressure measurements, and analysis of urinary and plasma electrolytes will be performed in conjunction with proteomic analysis. These parameters will be studied on a normal diet, and on diets in which sodium and potassium levels have been modified. The ability of thiazides to normalize any defects will be assessed. (2) Inducible, DCT-specific disruption of the mineralocorticoid receptor, to gain insight into the role of aldosterone in DCT function. These mice will be generated, and similarly to aim (1), blood pressure and electrolyte measurements will be performed under various dietary conditions. A didactic program in nephrology and in the responsible conduct of research will complement the research program to assist the candidate in achieving his long term career goal of performing independent basic nephrology research in an academic setting. Dr. David Ellison, a leader in DCT physiology will mentor the candidate's scientific development, as will input from Dr. Donald Kohan, a leader in mouse models of hypertension.

描述（由申请人提供）： 高血压影响着美国大约 25% 的成年人口，是中风、心肌梗塞、充血性心力衰竭和慢性肾病死亡的重要危险因素。肾脏的远曲小管 (DCT) 在钠的重吸收（主要通过氯化钠协同转运蛋白，NCC）以及血压调节中发挥着关键作用。 II 型假性醛固酮增多症 (PHAII) 就是最好的例证，其特征是高钾性高血压，是由 NCC 调节因子中增强其活性的基因缺陷引起的。 PHAII 可通过使用专门抑制 NCC 的噻嗪类利尿剂治疗来治愈。重要的是，噻嗪类利尿剂是大多数高血压患者的首选治疗选择，而不仅仅是 PHAII 患者的首选。关于 PHAII 是否仅由 NCC 活性改变引起，或者是否涉及其他离子通道和转运蛋白的失调，存在争议。还有证据表明 NCC 活性受盐皮质激素醛固酮调节。由于 DCT 中盐皮质激素受体的水平较低，因此醛固酮对该肾段的生理作用尚不清楚。该提案旨在表征两种小鼠模型，以便更好地了解 PHAII 和 DCT 功能。 (1)在DCT中过度表达NCC的小鼠的生成和分析，作为PHAII的可能模型。血压测量以及尿液和血浆电解质分析将与蛋白质组分析结合进行。这些参数将在正常饮食以及钠和钾水平已改变的饮食中进行研究。将评估噻嗪类药物使任何缺陷正常化的能力。 (2) 诱导性 DCT 特异性破坏盐皮质激素受体，以深入了解醛固酮在 DCT 功能中的作用。将生成这些小鼠，并且与目标（1）类似，将在各种饮食条件下进行血压和电解质测量。肾脏病学和负责任的研究行为的教学计划将补充研究计划，以帮助候选人实现在学术环境中进行独立基础肾脏病学研究的长期职业目标。 DCT 生理学领域的领导者 David Ellison 博士将指导候选人的科学发展，高血压小鼠模型领域的领导者 Donald Kohan 博士也将提供意见。