title: Cyclooxygenase 2 inhibition exacerbates AQP2 and pAQP2 downregulation independently of V2 receptor abundance in the postobstructed kidney.
abstract: Previously we demonstrated that ANG II receptor (AT1R) blockade attenuates V2 receptor (V2R), AQP2, and pS256-AQP2 downregulation in the postobstructed kidney and partially reverses obstruction-induced inhibition of cAMP generation and cyclooxygenase 2 (COX-2) induction. Therefore, we speculated whether the effects of AT1R blockade on V2R and the vasopressin-regulated pathway are attributable to attenuated COX-2 induction. To examine this, rats were subjected to 24-h bilateral ureteral obstruction (BUO) followed by 48-h release and treated with the COX-2 inhibitor parecoxib or saline. Control rats were sham-operated. Parecoxib treatment significantly reduced urine output 24 h after release of BUO whereas urine osmolality and solute-free water reabsorption was comparable between saline- and parecoxib-treated BUO rats. Immunoblotting revealed a significant decrease in AQP2 and pS256-AQP2 abundance to 20 and 23% of sham levels in parecoxib-treated BUO rats compared with 40 and 55% of sham levels in saline-treated BUO rats. Immunohistochemistry confirmed the exacerbated AQP2 and pS256-AQP2 downregulation in parecoxib-treated BUO rats. Finally, parecoxib treatment had no effect on V2R downregulation and the inhibited, vasopressin-stimulated cAMP generation in inner medullary membrane fractions from the postobstructed kidney. In conclusion, COX-2 inhibition exacerbates AQP2 and pS256-AQP2 downregulation 48 h after release of 24-h BUO independently of V2R abundance and vasopressin-stimulated cAMP generation. The results indicate that COX-2 inhibition does not mimic AT1R blockade-mediated effects and that AT1R-mediated AQP2 regulation in the postobstructed kidney collecting duct is independent of COX-2 induction.
authors.affiliation: The Water and Salt Research Center, Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark.
authors.forename: Anja M
authors.initials: AM
authors.lastname: Jensen
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Bae
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
authors.forename: Guixian
authors.initials: G
authors.lastname: Wang
authors.forename: Søren
authors.initials: S
authors.lastname: Nielsen
authors.forename: Horst
authors.initials: H
authors.lastname: Schweer
authors.forename: Soo Wan
authors.initials: SW
authors.lastname: Kim
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiaer
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1; D014667:Vasopressins / Q000494:pharmacology
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; D017483:Receptors, Vasopressin; C578716:Slc12a1 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D014667:Vasopressins; C409945:parecoxib; D000262:Adenylyl Cyclases