Hyponatremia is the most common electrolyte disorder of hospitalized patients in the United States and is a significant cause of morbidity and mortality. Clinical studies have provided important insights into this disorder, but many question remained unanswered about virtually every aspect of hyponatremia. Because controlled clinical trials are difficult and potentially dangerous in this population, studies using an animal model that mimics the clinical features of hyponatremia in human patients offers the best opportunity to better understand the pathophysiology of this disorder. During the first period of funding of this grant such an animal model was developed and is widely utilized for studies of experimental hyponatremia. During the second period of funding we employed this model to study how the brain adapts to hyponatremia, and the mechanisms that allow """"""""de-adaptation"""""""" once the hyponatremia is corrected to normonatremic levels. Although we now understand much more about the process of brain adaptation to and de-adaptation from hypoosmolar conditions, other tissues, particularly the kidney, must adapt to induced hypoosmolality as well. Perhaps the most important and unique way in which the kidney adapts is via renal escape from anti-diuresis. In both animal models of sustained AVP administration and patients with SIADH, water loading results in initial water retention and progressive hyponatremia which is then followed by escape from the induced anti-diuresis, which is characterized by increased free water excretion despite sustained administration of AVP, allowing water balance to be res-established and the serum [Na+] to be stabilized at a steady, albeit decreased, level. Although this phenomenon has been described since the earliest studies of AVP-induced anti-diuresis, there is at present no consensus regarding the cellular mechanisms underlying this important homeostatic response. In preliminary studies we have found a marked down-regulation of kidney aquaporin-2 protein and mRNA levels which correlate temporarily with the onset of renal escape from DDAVP-induced anti-diuresis. The present application proposes to study the extracellular, membrane, and intracellular mechanisms mediating this response. Specifically, we will: 1) characterize the changes in cortical and medullary kidney aquaporin-2 mRNA and protein expression during renal escape from anti-diuresis and following water restriction, 2) ascertain whether extracellular signals are involved with triggering the down-regulation of aquaporin-2 expression during renal escape from anti-diuresis, 3) determine whether changes in AVP receptor expression or binding correlate with changes in aquaporin-2 expression in inner medullary tissue during renal escape from anti- diuresis, and 4) study the cellular mechanisms associated with renal escape from anti-diuresis, and specifically whether decreased activity of the adenylate cyclase-cAMP cascade in the medulla accompanies the down- regulation of aquaporin-2 expression during this time. These studies should lead to an elucidation of the cellular mechanisms underlying one of the most basic and intriguing unanswered question about clinically hyponatremic disorders.
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