The pathological role of Bax in cisplatin nephrotoxicity
The pathological role of Bax in cisplatin nephrotoxicity
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DOI：
10.1038/sj.ki.5002256
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发表时间：
2007-07-01
影响因子：
19.6
通讯作者：
Dong, Z.
中科院分区：
文献类型：
--
作者：
Wei, Q.;Dong, G.;Dong, Z.
顺铂诱导的肾毒性涉及肾小管细胞坏死和细胞凋亡;后者可能由多种机制引发，包括内源性线粒体途径的激活。在培养的肾小管上皮细胞中，顺铂可激活促凋亡蛋白Bax，导致细胞色素c释放、半胱天冬酶激活和细胞凋亡。然而，缺乏Bax参与体内顺铂肾毒性的证据。我们分析了Bax调节顺铂肾毒性在野生型小鼠和确定Bax的病理作用，使用该基因被敲除的小鼠。在野生型小鼠中，顺铂诱导肾小管细胞中的Bax变得活跃，在线粒体中积累，并伴有急性肾损伤。与野生型小鼠相比，Bax基因敲除小鼠的肾功能（通过血尿素氮和血清肌酐测定）部分但显著保留。凋亡细胞数量减少，一般组织损伤。此外，顺铂诱导的细胞色素c的释放减弱，在β-缺陷小鼠。这种细胞凋亡和细胞色素c释放的显著减少也反映在Bax敲除动物制备的近端肾小管细胞的原代培养物中。总的来说，我们的研究结果提供了令人信服的证据Bax及其相关的凋亡途径在顺铂肾毒性的作用。
Nephrotoxicity induced by cisplatin involves tubular cell necrosis and apoptosis; the latter of which may be initiated by multiple mechanisms including activation of the intrinsic mitochondrial pathway. In cultured tubular epithelial cells, cisplatin can activate the proapoptotic protein Bax resulting in cytochrome c release, caspase activation, and apoptosis. Definitive evidence for the involvement of Bax in cisplatin nephrotoxicity in vivo, however, is lacking. We analyzed Bax regulation during cisplatin nephrotoxicity in wild-type mice and determined the pathological role of Bax using mice in which this gene was knocked out. In wild-type mice, cisplatin induced Bax in renal tubular cells which became active, accumulated in the mitochondria, and was accompanied by acute kidney injury. Compared with the wild-type mice renal function, as measured by blood urea nitrogen and serum creatinine, was partially but significantly preserved in Bax knockout mice. The number of apoptotic cells was decreased as was general tissue damage. Additionally, cisplatin-induced cytochrome c release was attenuated in the Bax-deficient mice. This significant decrease in apoptosis and in cytochrome c release was also mirrored in primary cultures of proximal tubular cells prepared from Bax knockout animals. Collectively, our results provide compelling evidence for a role of Bax and its related apoptotic pathway in cisplatin nephrotoxicity.