Differential Effect of COX1 and COX2 Inhibitors on Renal Outcomes following Ischemic Acute Kidney Injury
Differential Effect of COX1 and COX2 Inhibitors on Renal Outcomes following Ischemic Acute Kidney Injury
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DOI：
10.1159/000363251
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
Sauvant, Christoph
中科院分区：
文献类型：
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作者：
Bischoff, Ariane;Bucher, Michael;Sauvant, Christoph
背景/目标：我们先前已经表明，1 mg/kg吲哚美辛改善肾缺血后肾有机阴离子转运蛋白Oat 1和Oat 3的表达和功能，并进一步改善缺血后的肾结果。由于我们检测到COX 1或COX 2抑制剂对培养物中缺血和再灌注后有机阴离子转运的不同影响，我们研究了SC 560（COX 1抑制剂）和SC 58125（COX 2抑制剂）对缺血性急性肾损伤（iAKI）后Oat 1/3表达和肾脏结局的影响。研究方法：通过双侧夹闭肾动脉45分钟在大鼠中诱导iAKI。再灌注开始后立即腹腔内给予SC 560或SC 58125（各1 mg/kg）。假手术处理的动物作为对照。通过qPCR和Western印迹测定Oat 1/3。测定肾小球滤过率（GFR）、对氨基马尿酸（PAH）清除率和PAH提取率。缺血24 h后检测各项指标。计算肾血浆流量。结果：在钳夹动物中，SC 560（COX 1抑制剂）恢复了Oat 1/3的表达，以及肾灌注。此外，SC 560显著改善了通过GFR测量的肾功能。COX 2抑制剂SC 58125的应用没有发挥这些有益作用。结论：我们的研究表明，缺血后应用COX 1抑制剂5C 560可防止缺血诱导的再灌注期间Oat 1/3下调，并对肾功能具有实质性的保护作用。这种明显的功能改善是否以及在何种程度上是由于对肾小管功能、肾灌注或肾小球滤过的有益作用而产生的，将是未来研究的范围。(c)2014 S. Karger AG，巴塞尔
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). Methods: 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. Results: 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. Conclusion: Our study indicates that COX1 inhibitor 5C560 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 glonnerular filtration will be the scope of future studies. (c) 2014 S. Karger AG, Basel