title: COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice.
abstract: It was hypothesized that cyclooxygenase-2 (COX-2) activity promotes urine concentrating ability through stimulation of vasopressin (AVP) release after water deprivation (WD). COX-2-deficient (COX-2(-/-), C57BL/6) and wild-type (WT) mice were water deprived for 24 h, and water balance, central AVP mRNA and peptide level, AVP plasma concentration, and AVP-regulated renal transport protein abundances were measured. In male COX-2(-/-), basal urine output and water intake were elevated while urine osmolality was decreased compared with WT. Water deprivation resulted in lower urine osmolality, higher plasma osmolality in COX-2(-/-) mice irrespective of gender. Hypothalamic AVP mRNA level increased and was unchanged between COX-2(-/-) and WT after WD. AVP peptide content was higher in COX-2(-/-) compared with WT. At baseline, plasma AVP concentration was elevated in conscious chronically catheterized COX-2(-/-) mice, but after WD plasma AVP was unchanged between COX-2(-/-) and WT mice (43 ± 11 vs. 70 ± 16 pg/ml). Renal V2 receptor abundance was downregulated in COX-2(-/-) mice. Medullary interstitial osmolality increased and did not differ between COX-2(-/-) and WT after WD. Aquaporin-2 (AQP2; cortex-outer medulla), AQP3 (all regions), and UT-A1 (inner medulla) protein abundances were elevated in COX-2(-/-) at baseline and further increased after WD. COX-2(-/-) mice had elevated plasma urea and creatinine and accumulation of small subcapsular glomeruli. In conclusion, hypothalamic COX-2 activity is not necessary for enhanced AVP expression and secretion in response to water deprivation. Renal medullary COX-2 activity negatively regulates AQP2 and -3. The urine concentrating defect in COX-2(-/-) is likely caused by developmental glomerular injury and not dysregulation of AVP or collecting duct aquaporins.
authors: The Water and Salt Research Center, Institute of Clinical Medicine, University of Aarhus, Aarhus Univ. Hospital-Skejby, Brendstrupgaardsvej 100, Aarhus N, Denmark. rikke.norregaard@ki.au.dk
authors: Rikke
authors: R
authors: Nørregaard
authors: Kirsten
authors: K
authors: Madsen
authors: Pernille B L
authors: PB
authors: Hansen
authors: Peter
authors: P
authors: Bie
authors: Sugarna
authors: S
authors: Thavalingam
authors: Jørgen
authors: J
authors: Frøkiær
authors: Boye L
authors: BL
authors: Jensen
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000032:analysis; D051400:Aquaporin 3 / Q000032:analysis; D001127:Arginine Vasopressin / Q000097:blood / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007031:Hypothalamus / Q000201:enzymology; D007668:Kidney / Q000378:metabolism; D007671:Kidney Concentrating Ability; D008297:Male; D026901:Membrane Transport Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D017483:Receptors, Vasopressin / Q000032:analysis; D014508:Urea / Q000097:blood; D014868:Water Deprivation / Q000502:physiology; D014882:Water-Electrolyte Balance / Q000502:physiology; D000096982:Urea Transporters
chemical_list: D051399:Aquaporin 2; D051400:Aquaporin 3; D001127:Arginine Vasopressin; D003404:Creatinine; D051546:Cyclooxygenase 2; D026901:Membrane Transport Proteins; D017483:Receptors, Vasopressin; D014508:Urea; D000096982:Urea Transporters; C496024:Aqp2 protein, mouse; C496028:Aqp3 protein, mouse; C077623:Ptgs2 protein, mouse