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.
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