Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity independent on mitochondrial ROS production
Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity independent on mitochondrial ROS production
复制标题
Nrf2 激活可保护听毛细胞免受顺铂诱导的耳毒性，且与线粒体 ROS 产生无关
DOI：
10.1016/j.toxlet.2020.04.005
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发表时间：
2020-10-01
影响因子：
3.5
通讯作者：
Zheng, Yiqing
中科院分区：
文献类型：
--
作者：
Weijia, Zhang;Xiong, Hao;Zheng, Yiqing
顺铂是一种众所周知的常用化疗药物。然而，顺铂引起的耳毒性限制了其临床应用。以往的研究表明，活性氧（ROS）积累在顺铂诱导的耳毒性发病机制中起重要作用。在许多细胞类型中，转录因子、核因子红细胞2相关因子2 （Nrf2）和抗氧化反应元件（ARE）通过抑制ROS来保护细胞免受氧化应激的影响。我们的研究结果表明，顺铂损伤可降低HEI-OC1细胞中Nrf2的表达并抑制Nrf2的易位，Nrf2激活剂叔丁基对苯二酚（TBHQ）可通过抑制细胞总ROS积累使毛细胞免受顺铂诱导的凋亡。此外，我们发现TBHQ诱导的ROS积累减少并不依赖于线粒体来源的ROS产生，这表明Nrf2激活通过线粒体非依赖性的ROS产生减轻了顺铂诱导的氧化应激和细胞凋亡。因此，我们提供了一种通过激活Nrf2来预防和治疗顺铂诱导的耳毒性的潜在策略。综上所述，Nrf2激活通过抑制线粒体以外来源的细胞总ROS水平来保护听觉毛细胞免受顺铂诱导的耳毒性。
Cisplatin is a well-known and commonly used chemotherapeutic agent. However, cisplatin-induced ototoxicity limits its clinical use. Previous studies have shown an important role of reactive oxygen species (ROS) accumulation in the pathogenesis of cisplatin-induced ototoxicity. In many cell types, the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE) protect against oxidative stress by suppressing ROS. Here our results showed that cisplatin injury reduced Nrf2 expression and inhibited Nrf2 translocation in HEI-OC1 cells and Nrf2 activator tert-butylhydroquinone (TBHQ) rescued hair cells from cisplatin induced apoptosis by suppressing the total cellular ROS accumulation. Moreover, we found that decreased ROS accumulation induced by TBHQ didn't depend on mitochondrial derived ROS production, indicating that Nrf2 activation alleviated cisplatin induced oxidative stress and apoptosis through mitochondrial-independent ROS production. Therefore, we provide a potential strategy of prevention and treatment for cisplatin-induced ototoxicity by Nrf2 activation. In conclusion, Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity through suppressing the total cellular ROS levels which arise from sources other than mitochondria.