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 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.
Original language | English |
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Journal | American Journal of Physiology: Regulatory, Integrative and Comparative Physiology |
Volume | 298 |
Issue number | 4 |
Pages (from-to) | R1017-25 |
ISSN | 0363-6119 |
DOIs | |
Publication status | Published - Apr 2010 |
Externally published | Yes |
Keywords
- Animals
- Aquaporin 2
- Cyclooxygenase 1
- Cyclooxygenase 2
- Cyclooxygenase 2 Inhibitors
- Dinoprost
- Dinoprostone
- Immunohistochemistry
- Kidney
- Kidney Cortex
- Kidney Medulla
- Male
- Prostaglandin D2
- Prostaglandins
- Rats
- Rats, Wistar
- Thromboxane B2
- Ureteral Obstruction