A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo
A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo
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DOI：
10.1124/jpet.102.047522
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发表时间：
2003-06-01
影响因子：
3.5
通讯作者：
Makino, H
中科院分区：
文献类型：
--
作者：
Satoh, M;Kashihara, N;Makino, H
越来越多的证据表明，活性氧（ROS）引起的过氧化损伤可能是顺铂诱导的急性肾功能衰竭的发病机制之一。然而，很少有人知道氧自由基参与顺铂肾病。在这项研究中，我们研究了一种新的自由基清除剂，3-甲基-1-苯基-吡唑啉-5-酮（MCI-186;依达拉奉），对小鼠近端肾小管细胞（PTC）损伤诱导的顺铂在体外和肾功能在体内模型顺铂诱导的急性肾功能衰竭。依达拉朋以浓度依赖性方式（10（-5）至10（-3）M）抑制顺铂诱导的（40 μ M，24 h）细胞毒性。依达拉朋还减弱顺铂诱导的PTC的线粒体跨膜电位损失和ROS产生。在体内研究中，将雄性Wistar大鼠用顺铂（5 mg/kg，i. p.）和依达拉奉（1或5 mg/kg，i. v.）。治疗后5天检查依达拉奉对肾脏的影响。顺铂导致肾功能障碍、肾小管损伤、线粒体损伤（通过呼吸链复合物IV的组织化学染色测定）、肾蛋白氧化（使用含羰基蛋白的特异性抗体通过Western印迹分析检查）和肾小管细胞凋亡（通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记染色测定）。依达拉奉治疗可减轻上述变化。因此，依达拉奉在PTC中表现出细胞保护作用，并对顺铂表现出肾保护作用。我们的研究结果表明，ROS，特别是羟基自由基，参与顺铂肾病，依达拉奉可能是潜在的有用的保护肾脏和预防急性肾功能衰竭。
Accumulating evidence suggests that enhanced peroxidative damage caused by reactive oxygen species (ROS) may contribute to the pathogenesis of cisplatin-induced acute renal failure. Nevertheless, little is known about the involvement of oxygen radicals in cisplatin nephropathy. In this study, we investigated the effects of a novel free radical scavenger, 3-methyl-1-phenyl-pyrazolin-5-one (MCI-186; edarabone), on murine proximal tubular cell (PTC) damage induced by exposure to cisplatin in vitro and on renal function in an in vivo model of cisplatin-induced acute renal failure. Edarabone inhibited cisplatin-induced (40 muM, 24 h) cytotoxicity in a concentration-dependent manner (10(-5) to 10(-3) M). Edarabone also attenuated cisplatin-induced mitochondrial transmembrane potential loss and ROS production of PTCs. In the in vivo study, male Wistar rats were cotreated with cisplatin ( 5 mg/kg, i.p.) and edarabone (1 or 5 mg/kg, i.v.). Effects of edarabone on the kidney were examined 5 days after treatment. Cisplatin resulted in renal dysfunction, renal tubular damage, mitochondrial damage ( assayed by histochemical staining for respiratory chain complex IV), renal protein oxidation ( examined by Western blot analysis using a specific antibody for carbonyl group-containing proteins), and tubular apoptosis ( determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining). The above changes were attenuated by edarabone treatment. Thus, edarabone exhibited cytoprotective effects in PTCs and renoprotective effects against cisplatin. Our findings suggest that ROS, in particular hydroxyl radicals, are involved in cisplatin nephropathy and that edarabone may be potentially useful in protecting the kidneys and prevention of acute renal failure.