Pathophysiological roles of arginine vasopressin and aquaporin-2 in impaired water excretion and hyponatremia

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We examined the alteration in aquaporin-2 (AQP-2) water channel in pathological state of arginine vasopressin (AVP)-dependent hyponatremia. First, SIADH model was prepared in Sprague-Dawley rats by giving liquid diet and subcutaneous infusion of dDAVP. Serum Na level was decreased to below 120 mmol/l in the experimental SIADH rats, and urinary osmolality remained as low as 800-900 mmol/kg, that was significantly lower than that of 3,000-3,200 mmol/kg in the control rats. Thus, urinary concentrating defect was found, which is called as AVP escape phenomenon. There were marked reduction in AVP receptor binding and AVP V_2 receptor mRNA expression, but they were not different between the two groups. The expression of AQP-2 mRNA in kidney was upregulated in the SIADH rats, and its expression was significantly attenuated as compared to that in the dDAVP-excess rats, which were given solid diet and subcutaneous infusion of dDAVP. Similar results were obtained with kidney AQP-2 protein expression and urinary excretion of AQP-2. These in vivo studies indicate that either extracellular volume expansion or hypoosmolality may directly inhibit kidney AQP-2 mRNA expression, resulting in AVP escape in SIADH. Following in vitro study was carried out to examine whether osmolality directly regulate transcription of 5'-flanking region of AQP-2. The AQP-2 promoter gene (-9.5 kb) was obtained, and its activity was determined by luciferase assay. Cyclic AMP responsive element (CRE) was present until -1.1 kb. Hypertonic pressure of 600 mmol/kg increased the luciferase activity by approximately 2-fold in the AQP-2 promoter (-9.5〜-1.1 kb). Further study determined two osmolality responsive sites in the AQP-2 promoter gene (-9.5〜-7.7 kb and -6.0〜-4.2 kb).