Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue.
Inhibitors of cyclooxygenase (COX)-2 prevent suppression of aquaporin-2 and reduce polyuria in the acute phase after release of bilateral ureteral obstruction (BUO). We hypothesized that BUO leads to COX-2-mediated local accumulation of prostanoids in inner medulla (IM) tissue. To test this, rats were subjected to BUO and treated with selective COX-1 or COX-2 inhibitors. Tissue was examined at 2, 6, 12, and 24 h after BUO. COX-2 protein abundance increased in IM 12 and 24 h after onset of BUO but did not change in cortex. COX-1 did not change at any time points in any region. A full profile of all five primary prostanoids was obtained by mass spectrometric determination of PGE(2), PGF(2alpha), 6-keto-PGF(1alpha), PGD(2), and thromboxane (Tx) B(2) concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE(2), 6-keto-PGF(1alpha), and PGF(2alpha) was increased at 6 h BUO, and PGE(2) and PGF(2alpha) increased further at 12 h BUO. TxB(2) increased after 12 h BUO. 6-keto-PGF(1alpha) remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE(2,) TxB(2), 6-keto-PGF(1alpha), and PGF(2alpha) below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE(2), PGF(2alpha), and PGD(2) in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE(2) and 6-keto-PGF(1alpha) concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF(1alpha) and TxB(2) concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE(2) and PGF(2alpha) with minor, but significant, contributions from COX-1. PGD(2) synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.
Deptartment of Clinical Physiology and Nuclear Medicine, Aarhus University Hospital-Skejby, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark.
Rikke
R
Nørregaard
Boye L
BL
Jensen
Sukru Oguzkan
SO
Topcu
Guixian
G
Wang
Horst
H
Schweer
Søren
S
Nielsen
Jørgen
J
Frøkiaer
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000494:pharmacology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015230:Prostaglandin D2 / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000378:metabolism; D014517:Ureteral Obstruction / Q000201:enzymology / Q000503:physiopathology*
C496025:Aqp2 protein, rat; D051399:Aquaporin 2; D052246:Cyclooxygenase 2 Inhibitors; D011453:Prostaglandins; D013929:Thromboxane B2; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D015230:Prostaglandin D2