Bischoff Ariane, Bucher Michael, Gekle Michael, Sauvant Christoph
Klinik für Anästhesie und Operative Intensivmedizin, Universität Halle-Wittenberg, Halle, Germany.
Am J Nephrol. 2014;40(1):1-11. doi: 10.1159/000363251. Epub 2014 Jun 17.
BACKGROUND/AIMS: We have previously shown that 1 mg/kg indomethacin improves expression and functionality of renal organic anion transporters Oat1 and Oat3 after renal ischemia and furthermore improves renal outcome after ischemia. As we detected differential effects of COX1 or COX2 inhibitors on organic anion transport after ischemia and reperfusion in culture, we investigated the effect of the SC560 (COX1 inhibitor) and SC58125 (COX2 inhibitor) on expression of Oat1/3 and renal outcome after ischemic acute kidney injury (iAKI).
iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. SC560 or SC58125 (1 mg/kg each) were given intraperitoneally as soon as reperfusion started. Sham-treated animals served as controls. Oat1/3 were determined by qPCR and Western blot. Glomerular filtration rate (GFR), p-aminohippurate (PAH) clearance and PAH extraction ratio was determined. All parameters were detected 24 h after ischemia. Renal plasma flow was calculated.
In clamped animals SC560 (COX1 inhibitor) restored expression of Oat1/3, as well as renal perfusion. Additionally, SC560 substantially improved kidney function as measured by GFR. Application of the COX2 inhibitor SC58125 did not exert these beneficial effects.
Our study indicates that COX1 inhibitor SC560 applied after ischemia prevents ischemia-induced downregulation of Oat1/3 during reperfusion and has a substantial protective effect on kidney function. Whether and to what particular extent this apparent improvement of function is mechanistically due to beneficial effects on tubular function, renal perfusion or glomerular filtration will be the scope of future studies.
背景/目的：我们之前已经表明，1 mg/kg 吲哚美辛可改善肾缺血后肾有机阴离子转运体 Oat1 和 Oat3 的表达及功能，进而改善缺血后的肾脏结局。由于我们在培养中检测到 COX1 或 COX2 抑制剂对缺血再灌注后有机阴离子转运有不同影响，我们研究了 SC560（COX1 抑制剂）和 SC58125（COX2 抑制剂）对缺血性急性肾损伤（iAKI）后 Oat1/3 表达及肾脏结局的影响。
通过双侧夹闭肾动脉 45 分钟诱导大鼠发生 iAKI。再灌注一开始就腹腔注射 SC560 或 SC58125（各 1 mg/kg）。假手术处理的动物作为对照。通过定量聚合酶链反应（qPCR）和蛋白质免疫印迹法（Western blot）测定 Oat1/3。测定肾小球滤过率（GFR）、对氨基马尿酸（PAH）清除率和 PAH 提取率。在缺血后 24 小时检测所有参数。计算肾血浆流量。
在夹闭的动物中，SC560（COX1 抑制剂）恢复了 Oat1/3 的表达以及肾灌注。此外，通过 GFR 测量，SC560 显著改善了肾功能。应用 COX2 抑制剂 SC58125 未产生这些有益作用。
我们的研究表明，缺血后应用 COX1 抑制剂 SC560 可防止再灌注期间缺血诱导的 Oat1/3 下调，并对肾功能有显著保护作用。这种明显的功能改善在机制上是否以及在何种特定程度上归因于对肾小管功能、肾灌注或肾小球滤过的有益作用，将是未来研究的范围。
