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

Abstract

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 PGE2, PGF2α, 6-keto-PGF1α, PGD2, and thromboxane (Tx) B2 concentrations in kidney cortex/outer medulla and IM fractions. IM concentration of PGE2, 6-keto-PGF1α, and PGF2α was increased at 6 h BUO, and PGE2 and PGF2α increased further at 12 h BUO. TxB2 increased after 12 h BUO. 6-keto-PGF1α remained significantly increased after 24 h BUO. The COX-2 inhibitor parecoxib lowered IM PGE2, TxB2, 6-keto-PGF1α, and PGF2α below vehicle-treated BUO and sham rats at 6, 12 and, 24 h BUO. The COX-1 inhibitor SC-560 lowered PGE2, PGF2α, and PGD2 in IM compared with untreated 12 h BUO, but levels remained significantly above sham. In cortex tissue, PGE2 and 6-keto-PGF1α concentrations were elevated at 6 h only. In conclusion, COX-2 activity contributes to the transient increase in prostacyclin metabolite 6-keto-PGF1α and TxB2 concentration in the kidney IM, and COX-2 is the predominant isoform that is responsible for accumulation of PGE2 and PGF2α with minor, but significant, contributions from COX-1. PGD2 synthesis is mediated exclusively by COX-1. In BUO, therapeutic interventions aimed at the COX-prostanoid pathway should target primarily COX-2.