ANGIOTENSIN-VASOPRESSIN INTERACTIONS DURING ADAPTATION TO HYPOOSMOLALITY

描述(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，也是发病率和死亡率的主要原因。大多数低钠血症患者都是低渗血症，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困难且具有潜在危险，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好的机会。这个实验室开发了这样一个动物模型，我们和其他人已经成功地利用它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，以使患者在这种疾病中生存下来。肾脏最重要的适应方式是通过肾脏逃避抗利尿。在加压素(AVP)给药的动物模型和SLADH患者中，水负荷导致最初的水分保留和进行性低钠血症，随后是逃脱抗利尿。逃逸的特点是尽管持续服用AVP，但水排泄增加，使水重新平衡，并使血清[Na+]稳定在稳定的水平，尽管有所下降。虽然这一现象早在1950年代就已为人所知，但对于其根本机制还没有达成共识。我们最近发现，水通道蛋白和mRNA水平的显著下调，水通道蛋白-2(AQP2)，与肾逃避DDAVP诱导的抗利尿作用的开始存在时间上的相关性。我们实验室的后续研究强烈暗示AVP V2受体(V2R)的表达和结合下调，随后AVP刺激的肾脏集合管细胞中cAMP的产生被钝化，这可能是AQP2表达变化的原因。本申请旨在确定介导这一反应的系统、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组件之间的相互作用，既直接通过AVP V2R表达的变化，也间接通过全身血压和肾脏微循环的变化。这些研究将更好地了解从整体血液动力学到细胞反应的综合机制，为患者提供最基本和最重要的生理防御，使患者能够在低渗障碍中生存。

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.