Amelioration of cisplatin-induced nephrotoxicity in peroxiredoxin I-deficient mice
Amelioration of cisplatin-induced nephrotoxicity in peroxiredoxin I-deficient mice
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DOI：
10.1007/s00280-012-2046-0
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发表时间：
2013-02-01
影响因子：
3
通讯作者：
Yanagawa, Toru
中科院分区：
文献类型：
--
作者：
Okada, Kosuke;Ma, Dongmei;Yanagawa, Toru
顺铂是用于治疗癌症的最有效的化学治疗剂之一。然而，顺铂诱导的肾毒性是一个严重的问题，其部分原因是氧化损伤。我们以前表明，小鼠胚胎成纤维细胞缺乏过氧化物酶I（Prx I），一个主要的Nrf2连接的抗氧化酶，是顺铂诱导的细胞毒性敏感。在本研究中，我们研究了Prx I对顺铂诱导的肾损伤在体内使用Prx I-null小鼠。Prx I-null小鼠和野生型（WT）小鼠腹腔注射顺铂，并取出组织，并进行组织病理学评价。此外，外排转运蛋白的基因和蛋白表达进行了分析。在体外细胞研究中，Prx I-null小鼠表现出较少的顺铂诱导的肾损伤比WT小鼠在组织学和血液生化分析。此外，Prx I基因敲除小鼠腹腔注射顺铂后，顺铂的清除率高于WT小鼠。与这些结果相一致，在基础和顺铂诱导条件下，与WT小鼠相比，Prx I缺失小鼠的肾外排转运蛋白Mrp2和Mrp4表达更高。我们认为，在Prx I基因敲除小鼠中，c-Myc的转录活性增强可能部分地促进了肾外排转运蛋白的表达增强。总之，顺铂清除率的提高显著减轻了Prx I基因敲除小鼠的肾毒性。
Cisplatin is one of the most potent chemotherapeutic agents used to treat cancer. However, cisplatin-induced nephrotoxicity, which is partly caused by oxidative damage, is a serious problem. We previously showed that murine embryonic fibroblasts deficient in Peroxiredoxin I (Prx I), a major Nrf2-linked anti-oxidant enzyme, are susceptible to cisplatin-induced cytotoxicity. In the present study, we examined the role of Prx I against cisplatin-induced renal injury in vivo using Prx I-null mice.Prx I-null mice and wild-type (WT) mice were given an intraperitoneal injection of cisplatin, and tissues were removed and evaluated histopathologically. In addition, gene and protein expression of efflux transporters was analyzed.In contrast to an in vitro cell study, Prx I-null mice exhibited less cisplatin-induced renal damage than WT mice in histological and blood biochemical analyses. Moreover, Prx I-null mice showed a higher clearance rate of cisplatin than WT mice following intraperitoneal cisplatin injection. Consistent with these results, Prx I-null mice exhibited higher expression of renal efflux transporters Mrp2 and Mrp4 compared with WT mice under both basal and the cisplatin-induced conditions. We suggest the enhanced transcriptional activity of c-Myc in Prx I-null mice may partly contribute the enhanced expression of renal efflux transporters.In summary, the enhanced clearance rate of cisplatin significantly attenuates nephrotoxicity in Prx I-null mice.