title: Disruption of cyclooxygenase-2 prevents downregulation of cortical AQP2 and AQP3 in response to bilateral ureteral obstruction in the mouse.
abstract: Bilateral ureteral obstruction (BUO) in rats is associated with increased cyclooxygenase type 2 (COX-2) expression, and selective COX-2 inhibition prevents downregulation of aquaporins (AQPs) in response to BUO. It was hypothesized that a murine model would display similar changes in renal COX-2 and AQPs upon BUO and that targeted disruption of COX-2 protects against BUO-induced suppression of collecting duct AQPs. COX-2(-/-) and wild-type littermates (C57BL/6) were employed to determine COX-1, -2, AQP2, and AQP3 protein abundances and localization after BUO. In a separate series, sham and BUO wild-type mice were treated with a selective COX-2 inhibitor, parecoxib. The COX-2 protein level increased in wild-type mice in response to BUO and was not detectable in COX-2(-/-). COX-1 protein abundance was increased in sham-operated and BUO mice. Total AQP2 and -3 mRNA and protein levels decreased significantly after BUO in the cortex+outer medulla (C+OM) and inner medulla (IM). The decrease in C+OM AQP2 and -3 levels was attenuated/prevented in COX-2(-/-) mice, whereas there was no change in the IM. In parallel, inhibition of COX-2 by parecoxib rescued C+OM AQP3 and IM AQP2 protein level in wild-type mice subjected to BUO. In summary, 1) In C57BL/6 mice, ureteral obstruction increases renal COX-2 expression in interstitial cells and lowers AQP2/-3 abundance and 2) inhibition of COX-2 activity by targeted disruption or pharmacological blockade attenuates obstruction-induced AQP downregulation. In conclusion, COX-2-derived prostaglandins contribute to downregulation of transcellular water transporters in the collecting duct and likely to postobstruction diureses in the mouse.
authors.affiliation: The Water and Salt Research Center, Institute of Clinical Medicine, Aarhus University. Hospital-Skejby, Brendstrupgaardsvej 100, Aarhus N, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Nilsson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Madsen
authors.forename: Sukru Oguzkan
authors.initials: SO
authors.lastname: Topcu
authors.forename: Boye L
authors.initials: BL
authors.lastname: Jensen
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
mesh_terms: D000818:Animals; D051399:Aquaporin 2 / Q000096:biosynthesis* / Q000235:genetics; D051400:Aquaporin 3 / Q000096:biosynthesis* / Q000235:genetics; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000502:physiology; D007672:Kidney Cortex / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D014517:Ureteral Obstruction / Q000378:metabolism*
chemical_list: C496024:Aqp2 protein, mouse; C496028:Aqp3 protein, mouse; D051399:Aquaporin 2; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D051400:Aquaporin 3; D012313:RNA; C409945:parecoxib; D051546:Cyclooxygenase 2