Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue

Norregaard R, Jensen BL, Topcu SO, Wang G, Schweer H, Nielsen S, Frokiaer J. Urinary tract obstruction induces transient accumulation of COX-2-derived prostanoids in kidney tissue. Am J Physiol Regul Integr Comp Physiol 298: R1017-R1025, 2010. First published February 10, 2010; doi: 10.1152/ajpregu.00336.2009.-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(2 alpha), 6-keto-PGF(1 alpha), PGD(2), and thromboxane (Tx) B-2 concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE(2), 6-keto-PGF(1 alpha), and PGF(2 alpha) was increased at 6 h BUO, and PGE(2) and PGF(2 alpha) increased further at 12 h BUO. TxB(2) increased after 12 h BUO. 6-keto-PGF(1 alpha) remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE(2), TxB(2), 6-keto-PGF(1 alpha), and PGF(2 alpha) below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE(2), PGF(2 alpha), 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(1 alpha) concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF(1 alpha) 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(2 alpha) 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.