Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity
Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity
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DOI：
10.1038/ki.2012.64
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发表时间：
2012-07-01
影响因子：
19.6
通讯作者：
Padanilam, Babu J.
中科院分区：
文献类型：
--
作者：
Kim, Jinu;Long, Kelly E.;Padanilam, Babu J.
细胞凋亡、坏死和炎症是顺铂肾毒性的标志;然而，坏死和炎症的作用和机制仍不明确。由于聚（ADP-核糖）聚合酶1（PARP 1）抑制或其基因缺失在几种肾脏疾病模型中具有肾脏保护作用，我们测试了其激活是否可能参与顺铂肾毒性。发现Parp 1缺乏可减少顺铂诱导的肾功能障碍、氧化应激和肾小管坏死，但不能减少细胞凋亡。此外，中性粒细胞浸润，核因子-κ B，c-Jun N-末端激酶，p38丝裂原活化蛋白激酶的激活，和促炎基因的上调都废除了Parp 1缺陷。使用从Parp 1缺陷型和野生型小鼠中分离的近端小管上皮细胞和药理学抑制剂，我们发现了顺铂损伤后PARP 1/Toll样受体4/p38/肿瘤坏死因子-α轴的证据。此外，PARP 1的药理学抑制可防止顺铂诱导的肾脏结构/功能损伤和炎症。因此，我们的研究结果表明，PARP 1激活是一个主要的信号，其抑制/损失保护顺铂诱导的肾毒性。靶向PARP 1可能为顺铂肾毒性提供潜在的治疗策略。Kidney International（2012）82，193-203; doi：10.1038/ki.2012.64; 2012年3月21日在线发表
Apoptosis, necrosis, and inflammation are hallmarks of cisplatin nephrotoxicity; however, the role and mechanisms of necrosis and inflammation remains undefined. As poly(ADP-ribose) polymerase 1 (PARP1) inhibition or its gene deletion is renoprotective in several renal disease models, we tested whether its activation may be involved in cisplatin nephrotoxicity. Parp1 deficiency was found to reduce cisplatin-induced kidney dysfunction, oxidative stress, and tubular necrosis, but not apoptosis. Moreover, neutrophil infiltration, activation of nuclear factor-kappa B, c-Jun N-terminal kinases, p38 mitogen-activated protein kinase, and upregulation of proinflammatory genes were all abrogated by Parp1 deficiency. Using proximal tubule epithelial cells isolated from Parp1-deficient and wild-type mice and pharmacological inhibitors, we found evidence for a PARP1/Toll-like receptor 4/p38/tumor necrosis factor-alpha axis following cisplatin injury. Furthermore, pharmacological inhibition of PARP1 protected against cisplatin-induced kidney structural/functional damage and inflammation. Thus, our findings suggest that PARP1 activation is a primary signal and its inhibition/loss protects against cisplatin-induced nephrotoxicity. Targeting PARP1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity. Kidney International (2012) 82, 193-203; doi: 10.1038/ki.2012.64; published online 21 March 2012