Cyclooxygenase 2 inhibition exacerbates AQP2 and pAQP2 downregulation independently of V2 receptor abundance in the postobstructed kidney.
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.
Jensen
Anja M
AM
The Water and Salt Research Center, Institute of Clinical Medicine, University of Aarhus, Aarhus, Denmark.
Bae
Eun Hui
EH
Nørregaard
Rikke
R
Wang
Guixian
G
Nielsen
Søren
S
Schweer
Horst
H
Kim
Soo Wan
SW
Frøkiaer
Jørgen
J
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
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