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:10.11 152/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-I 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 PG[E.sub.2], PG[F.sub.2[alpha]], 6-keto-PG[F.sub.1[alpha]], PG[D.sub.2], and thromboxane (Tx) [B.sub.2] concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PG[E.sub.2], 6-keto-PG[F.sub.1[alpha]], and PG[F.sub.2[alpha]] was increased at 6 h BUO, and PG[E.sub.2] and PG[F.sub.2[alpha]] increased further at 12 h BUO. Tx[B.sub.2] increased after 12 h BUO. 6-keto-PG[F.sub.1[alha]] remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PG[E.sub.2]. Tx[B.sub.2], 6-keto-PG[F.sub.1[alpha]], and PG[F.sub.2[alpha]] below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PG[E.sub.2], PG[F.sub.2[alpha]], and PG[D.sub.2] in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PG[E.sub.2] and 6-keto-PG[F1[alpha]] concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PG[F.sub.1[alpha]] and Tx[B.sub.2] concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE2 and PG[F.sub.2[alpha]] with minor, but significant, contributions from COX-1. PG[D.sub.2] synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COXprostanoid pathway should target primarily COX-2. bilateral ureteral obstruction; cyclooxygenase-2; mass spectrometric doi: 10.1152/Npregu.00336.2009.