Yin Xiaoyan, Apostolov Eugene O, Shah Sudhir V, Wang Xiaoying, Bogdanov Konstantin V, Buzder Timea, Stewart Anna G, Basnakian Alexei G
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
J Am Soc Nephrol. 2007 Sep;18(9):2544-53. doi: 10.1681/ASN.2006080896. Epub 2007 Aug 5.
Nephrotoxicity from the chemotherapeutic drug cisplatin is associated with DNA fragmentation and cell death. We have recently demonstrated that DNase I knockout mice are significantly protected against cisplatin nephrotoxicity, but it is unknown whether the DNA fragmentation that occurs is produced by DNase I or another endonuclease. In this study we assessed the expression of several endonucleases involved in cell death after injection of cisplatin and found that the expression of endonuclease G (EndoG) increased whereas the expression of DNase I decreased almost to zero. Immunostaining showed that some nuclei contained both fragmented DNA and EndoG, suggesting that EndoG may cause DNA fragmentation induced by cisplatin. The increase in expression of EndoG was greater in wild-type mice than in DNase I knockout mice, indicating a potential link between the two endonucleases. In support of such a link, overexpression of DNase I in cultured mouse tubular epithelial cells also induced EndoG. Furthermore, gene silencing of EndoG in vitro provided significant protection against cell death. Taken together, our data suggest that both DNase I and EndoG mediate cisplatin injury to tubular epithelial cells.
化疗药物顺铂引起的肾毒性与DNA片段化和细胞死亡有关。我们最近证明，DNA酶I基因敲除小鼠对顺铂肾毒性具有显著的保护作用，但尚不清楚所发生的DNA片段化是由DNA酶I还是其他核酸内切酶产生的。在本研究中，我们评估了注射顺铂后参与细胞死亡的几种核酸内切酶的表达，发现核酸内切酶G（EndoG）的表达增加，而DNA酶I的表达几乎降至零。免疫染色显示，一些细胞核同时含有片段化DNA和EndoG，这表明EndoG可能导致顺铂诱导的DNA片段化。野生型小鼠中EndoG表达的增加比DNA酶I基因敲除小鼠更大，表明这两种核酸内切酶之间存在潜在联系。为支持这种联系，在培养的小鼠肾小管上皮细胞中过表达DNA酶I也可诱导EndoG。此外，体外对EndoG进行基因沉默可显著保护细胞免于死亡。综上所述，我们的数据表明，DNA酶I和EndoG均介导顺铂对肾小管上皮细胞的损伤。
