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Molecular analysis of impaired urinary diluting capacity in glucocorticoid deficiency

Departments of ¹Medicine and ²Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado; and ³Division of Critical Care Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan

Submitted 30 August 2005 ; accepted in final form 5 December 2005

Urinary diluting ability and protein abundance of renal aquaporins (AQPs) and ion transporters in glucocorticoid-deficient (GD) rats were examined at baseline and in response to oral water loading. Rats underwent bilateral adrenalectomy followed by aldosterone (GD) or aldosterone + dexamethasone (CTL) replacement. Before oral water loading, urinary output was significantly decreased and urinary osmolality (U_osm) was increased in GD compared with CTL rats. Protein abundance of inner medullary AQP2 (148 ± 18%), phosphorylated AQP2 (pAQP2, 156 ± 13%), and AQP3 (145 ± 8%) was significantly upregulated in GD compared with CTL rats (all P < 0.05). GD rats also demonstrated a marked reduction in urinary Na⁺ excretion compared with pair-fed CTL rats. Na⁺-K⁺-2Cl^– cotransporter, Na⁺/H⁺ exchanger type 3, and cortical - and -subunits of the epithelial Na⁺ channel were significantly upregulated in GD rats. At 1 h after an acute water load (40 ml/kg by oral gavage), GD rats demonstrated a decrease in percent water excretion (5 ± 1 vs. 33 ± 9%, P < 0.01) and urinary output (33 ± 12 vs. 250 ± 65 µl·kg^–1·min^–1, P < 0.05) and an increase in U_osm (1,894 ± 292 vs. 316 ± 92 mosmol/kgH₂O, P < 0.001) compared with CTL rats. Plasma AVP was increased (1.6 ± 0.2 vs. 0.9 ± 0.2 pg/ml, P < 0.05), as was protein expression of inner medullary AQP2 (149 ± 5%) and pAQP2 (177 ± 9%, P < 0.01), in GD compared with CTL rats; apical expression of AQP2 was maintained in GD rats. The vasopressin V₂ receptor antagonist OPC-31260 increased percent water excretion and urinary output and reduced U_osm compared with vehicle-treated GD rats. OPC-31260 also reversed the increased abundance and apical trafficking of inner medullary AQP2 and pAQP2 protein in GD rats. In conclusion, enhanced protein abundance of Na⁺ transporters and Na⁺ channels with Na⁺ retention occurred with GD. OPC-31260 reversed upregulation and apical trafficking of AQP2 and pAQP2 in association with improved urinary diluting capacity and increased water excretion after oral water loading.

arginine vasopressin; aquaporin; impaired urinary dilution

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