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

基本信息

批准号：
7259723
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
项目类别：
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/7259723
关键词：
2&apos ,3&apos -Dideoxyadenosine Acute Address Aldosterone Angiotensin II Angiotensins Animal Model Argipressin Binding Blood Pressure Brain Cells Chronic Clinical Condition Consensus Controlled Clinical Trials Cyclic AMP Data Disease Distal Down-Regulation Electrolyte Disorder Elevation 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 Transcriptional Activation Transgenic Mice Tubular formation Ultrasonics Up-Regulation V2 Receptors Vasopressins Water Whole Organism antidiuresis aquaporin-2 base 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

项目摘要

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，也是发病和死亡的主要原因。大多数低钠血症患者都是低渗性的，反映了这种疾病的稀释基础。由于对照临床试验在该人群中非常困难且存在潜在危险，因此使用模拟稀释性低钠血症临床特征的动物模型进行的研究为了解这种疾病的病理生理学提供了最佳机会。该实验室开发了这样一种动物模型，我们和其他人已成功地利用该模型来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，以便患者能够在这种疾病中生存。肾脏适应的最重要方式是通过肾脏逃避抗利尿作用。在使用加压素 (AVP) 的动物模型和 SlADH 患者中，水负荷会导致最初的水潴留和进行性低钠血症，随后会逃避抗利尿作用。逃逸的特点是，尽管持续施用 AVP，但水排泄增加，并且允许重新建立水平衡，并且血清 [Na+] 稳定在稳定的（尽管有所下降）水平。尽管这种现象自 20 世纪 50 年代以来就已为人所知，但对于其潜在机制尚未达成共识。我们最近发现，水通道水通道蛋白-2 (AQP2) 的蛋白质和 mRNA 水平显着下调，与 dDAVP 诱导的抗利尿作用中肾逃逸的发生在时间上相关。我们实验室的后续研究强烈表明 AVP V2 受体 (V2R) 表达和结合的下调，随后肾集合管细胞中 AVP 刺激的 cAMP 产生减弱，这可能是 AQP2 表达变化的原因。本申请提出鉴定介导该反应的全身性、肾内和细胞内机制，特别是肾素-血管紧张素-醛固酮和加压素系统的成分之间的相互作用，直接地通过AVP V2R表达的变化，以及间接地通过全身性的变化来确定。血压和肾脏微循环。这些研究将更好地理解从整个生物体血流动力学到细胞反应的整合机制，这些机制是最基本和临床上重要的生理防御的基础，使患者能够在低渗性疾病中生存。