ANGIOTENSIN-VASOPRESSIN INTERACTIONS DURING ADAPTATION TO HYPOOSMOLALITY

适应低渗透压期间血管紧张素-加压素的相互作用

• 批准号: 7596208
• 负责人: JOSEPH G VERBALIS
• 金额: $ 34.92万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596208
• 关键词: Acute; Address; Aldosterone; Angiotensin II; Angiotensins; Animal Model; Argipressin; Binding; Blood Pressure; Brain; Cells; Chronic; Clinical; Consensus; Controlled Clinical Trials; Cyclic AMP; Data; Disease; Distal; Down-Regulation; Electrolyte Disorder; Equilibrium; Excretory function; Functional disorder; Genes; Hyponatremia; Kidney; Knock-out; Knowledge; Laboratories; Ligand Binding; Magnetic Resonance Imaging; Maintenance; Measures; Mediating; Mediator of activation protein; Medicine; Messenger RNA; Microcirculation; Modeling; Morbidity - disease rate; Natriuresis; Nitric Oxide; Patients; Physiological; Physiological Processes; Play; Population Study; Process; Production; Protein Binding; Protein Isoforms; Proteins; Rattus; Regulation; Renal Blood Flow; Renin; Renin-Angiotensin-Aldosterone System; Research Personnel; Role; Serum; Signal Transduction; Sodium; System; Tissues; Transgenic Mice; Tubular formation; Ultrasonics; Up-Regulation; V2 Receptors; Vasopressins; Water; Whole Organism; antidiuresis; aquaporin-2; base; clinical practice; collecting tubule structure; dilutional hyponatremia; hemodynamics; iron oxide; kidney cortex; mortality; mouse model; progesterone 11-hemisuccinate-(2-iodohistamine); programs; protein expression; receptor; receptor expression; research study; response; water channel

DESCRIPTION (provided by applicant): Hyponatremia is the most common electrolyte disorder of hospitalized patients in the U.S. and is a major cause of morbidity and mortality. Most hyponatremic patients are hypoosmolar, reflecting the dilutional basis of this disorder. Because controlled clinical trials are difficult and potentially dangerous in this population, studies using an animal model that mimics the clinical features of dilutional hyponatremia offer the best opportunity to understand the pathophysiology of this disorder. This laboratory has developed such an animal model that we and others have successfully employed to study how the brain adapts to acute and chronic hypoosmolality. Other tissues, particularly the kidney, must adapt to hypoosmolality as well in order for patients to survive this disorder. The most important way in which the kidney adapts is via renal escape from antidiuresis. In animal models of vasopressin (AVP) administration and patients with SlADH, water loading results in initial water retention and progressive hyponatremia, which is then followed by escape from the antidiuresis. Escape is characterized by increased water excretion despite sustained administration of AVP, and allows water balance to be re-established and the serum [Na+] to be stabilized at a steady, albeit decreased, level. Although this phenomenon has been known since the 1950s, there was no consensus regarding the underlying mechanism. We recently discovered that a marked down-regulation of protein and mRNA levels of the water channel, aquaporin-2 (AQP2), correlated temporally with the onset of renal escape from dDAVP-induced antidiuresis. Subsequent studies from our laboratory have strongly implicated down- regulation of AVP V2 receptor (V2R) expression and binding, with subsequent blunted AVP-stimulated cAMP production in kidney collecting duct cells, as a likely cause of the changes in AQP2 expression. The present application proposes to identify the systemic, intrarenal and intracellular mechanisms mediating this response, and specifically the interactions between components of the renin-angiotensin-aldosterone and vasopressin systems both directly, via changes in AVP V2R expression, and indirectly, through changes in systemic blood pressure and the renal microcirculation. These studies will provide a better understanding of the integrative mechanisms, from whole organism hemodynamics to cellular responses, underlying the most basic and clinically important physiological defense that allows patients to survive hypoosmolar disorders.

描述（由申请人提供）：低钠血症是美国住院患者最常见的电解质紊乱，是发病率和死亡率的主要原因。大多数低钠血症患者是低渗性的，反映了这种疾病的稀释基础。由于对照临床试验在这一人群中是困难的和潜在的危险，使用动物模型的研究，模拟稀释性低钠血症的临床特征提供了最好的机会，了解这种疾病的病理生理学。这个实验室已经开发了这样一种动物模型，我们和其他人已经成功地用于研究大脑如何适应急性和慢性低渗透压。其他组织，特别是肾脏，也必须适应低渗透压，以便患者在这种疾病中生存。肾脏适应的最重要方式是通过肾脏逃避抗利尿剂。在血管加压素（AVP）给药的动物模型和SlADH患者中，水负荷导致初始水潴留和进行性低钠血症，然后逃避抗利尿剂。逃逸的特征在于尽管持续施用AVP，但水排泄增加，并且允许水平衡重新建立，血清[Na+]稳定在稳定但降低的水平。虽然这种现象自1950年代以来就已为人所知，但对于其内在机制尚未达成共识。我们最近发现，水通道，水通道蛋白-2（AQP 2）的蛋白质和mRNA水平的显著下调与dDAVP诱导的抗利尿作用的肾逃逸的发生时间相关。我们实验室的后续研究强烈暗示AVP V2受体（V2 R）表达和结合的下调，以及随后肾脏集合管细胞中AVP刺激的cAMP产生的钝化，作为AQP 2表达变化的可能原因。本申请提出鉴定介导该反应的全身性、肾内和细胞内机制，特别是通过AVP V2 R表达的变化直接地和通过全身血压和肾微循环的变化间接地鉴定肾素-血管紧张素-醛固酮和加压素系统的组分之间的相互作用。这些研究将提供一个更好的理解的综合机制，从整个生物体的血流动力学细胞反应，最基本的和临床上重要的生理防御，使患者生存低渗性疾病的基础。