ANGIOTENSIN-VASOPRESSIN INTERACTIONS DURING ADAPTATION TO HYPOOSMOLALITY

描述（由申请人提供）：低钠血症是美国住院患者中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钠血症，反映了这种疾病的稀释基础。由于在这一人群中进行对照临床试验是困难的，而且有潜在的危险，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。这个实验室已经开发出这样一种动物模型，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。其他组织，特别是肾脏，也必须适应低渗，以便患者在这种疾病中存活下来。肾脏适应的最重要的方式是通过肾逃避抗利尿。在抗利尿激素（AVP）给药和SlADH患者的动物模型中，水负荷导致初始水潴留和进行性低钠血症，随后从抗利尿中逃逸。逃逸的特点是尽管持续服用AVP，但水排泄增加，并允许水平衡重新建立，血清[Na+]稳定在稳定（尽管下降）水平。虽然这一现象自20世纪50年代以来就已为人所知，但对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）的蛋白和mRNA水平的显著下调与ddavp诱导的抗利尿肾逃逸的发生在时间上相关。我们实验室的后续研究强烈暗示了AVP V2受体（V2R）表达和结合的下调，随后AVP刺激的肾收集管细胞中cAMP的产生减弱，这可能是AQP2表达变化的原因。本研究旨在确定介导这种反应的全身、肾内和细胞内机制，特别是肾素-血管紧张素-醛固酮和血管加压素系统组分之间的相互作用，这两种相互作用直接通过AVP V2R表达的变化，间接通过全身血压和肾脏微循环的变化。这些研究将提供一个更好的理解综合机制，从整个生物体的血流动力学到细胞反应，潜在的最基本和临床重要的生理防御，使患者生存的低渗功能障碍。

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.