Deptartment of Clinical Physiology and Nuclear Medicine, Aarhus University Hospital-Skejby, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark.
Am J Physiol Regul Integr Comp Physiol. 2010 Apr;298(4):R1017-25. doi: 10.1152/ajpregu.00336.2009. Epub 2010 Feb 10.
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.
环氧化酶（COX）-2 抑制剂可防止水通道蛋白-2 的抑制，并减少双侧输尿管梗阻（BUO）后急性期的多尿。我们假设 BUO 导致 COX-2 介导的前列腺素在内髓质（IM）组织中的局部积累。为了验证这一点，将大鼠进行 BUO 处理，并使用选择性 COX-1 或 COX-2 抑制剂进行治疗。在 BUO 后 2、6、12 和 24 小时检查组织。COX-2 蛋白丰度在 BUO 发作后 12 和 24 小时增加，但在皮质中没有变化。在任何区域的任何时间点，COX-1 均未改变。通过质谱法测定肾皮质/外髓质和 IM 级分中 PGE（2），PGF（2alpha），6-酮-PGF（1alpha），PGD（2）和血栓素 B（2）浓度，获得了所有五种主要前列腺素的完整图谱。BUO 后 6 小时 IM 中 PGE（2），6-酮-PGF（1alpha）和 PGF（2alpha）的浓度增加，BUO 后 12 小时 PGE（2）和 PGF（2alpha）的浓度进一步增加。BUO 后 12 小时 TxB（2）增加。BUO 后 24 小时 6-酮-PGF（1alpha）仍显着增加。COX-2 抑制剂帕瑞昔布可将 IM PGE（2），TxB（2），6-酮-PGF（1alpha）和 PGF（2alpha）降低至与 BUO 和假手术大鼠的载体处理相比，BUO 后 6、12 和 24 小时。COX-1 抑制剂 SC-560 降低了 IM 中与未经处理的 12 小时 BUO 相比 PGE（2），PGF（2alpha）和 PGD（2）的浓度，但水平仍显着高于假手术。在皮质组织中，仅在 6 小时时 PGE（2）和 6-酮-PGF（1alpha）浓度升高。总之，COX-2 活性有助于肾脏 IM 中前列腺素代谢物 6-酮-PGF（1alpha）和 TxB（2）浓度的短暂增加，并且 COX-2 是负责 PGE（2）和 PGF（2alpha）积累的主要同工酶，而 COX-1 则具有较小但重要的贡献。PGD（2）合成仅由 COX-1 介导。在 BUO 中，针对 COX-前列腺素途径的治疗干预应主要针对 COX-2。
