Genetic Evidence of an Evolutionarily Conserved Role for Nrf2 in the Protection against Oxidative Stress
Genetic Evidence of an Evolutionarily Conserved Role for Nrf2 in the Protection against Oxidative Stress
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DOI：
10.1128/mcb.00481-12
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发表时间：
2012-11-01
影响因子：
5.3
通讯作者：
Kobayashi, Makoto
中科院分区：
文献类型：
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作者：
Mukaigasa, Katsuki;Nguyen, Linh T. P.;Kobayashi, Makoto
转录因子Nrf2被认为是哺乳动物抗氧化防御的主要调节因子。然而，目前还不清楚这一概念是否适用于非哺乳类脊椎动物，因为没有动物模型以外的Nrf2基因敲除小鼠已产生检查Nrf2缺陷的影响。在这里，我们的特点是一个隐性的Nrf2（nrf2（fh318））在较低的脊椎动物，斑马鱼（斑马鱼）的功能丧失突变体。与小鼠模型中的发现一致，nrf2（fh318）突变体显示出对氧化应激和亲电子体的Nrf2靶基因的诱导减少，但存活和可育，其胚胎发育正常。nrf2（fh318）幼虫表现出增强的敏感性，氧化应激和亲电，特别是过氧化物，和预处理与Nrf2激活化合物，萝卜硫素，降低过氧化物诱导的致死性在野生型，但不是nrf2（fh318）突变体，表明抗氧化应激是高度依赖于Nrf2功能。这些结果揭示了脊椎动物Nrf2在保护免受氧化应激方面的进化保守作用。有趣的是，野生型和nrf2（fh318）幼虫之间没有显着差异，就其对超氧化物和单线态氧发生器的敏感性，这表明Nrf2在氧化应激保护中的重要性根据活性氧（ROS）的类型而变化。
Transcription factor Nrf2 is considered a master regulator of antioxidant defense in mammals. However, it is unclear whether this concept is applicable to nonmammalian vertebrates, because no animal model other than Nrf2 knockout mice has been generated to examine the effects of Nrf2 deficiency. Here, we characterized a recessive loss-of-function mutant of Nrf2 (nrf2(fh318)) in a lower vertebrate, the zebrafish (Danio rerio). In keeping with the findings in the mouse model, nrf2(fh318) mutants exhibited reduced induction of the Nrf2 target genes in response to oxidative stress and electrophiles but were viable and fertile, and their embryos developed normally. The nrf2(fh318) larvae displayed enhanced sensitivity to oxidative stress and electrophiles, especially peroxides, and pretreatment with an Nrf2-activating compound, sulforaphane, decreased peroxide-induced lethality in the wild type but not nrf2(fh318) mutants, indicating that resistance to oxidative stress is highly dependent on Nrf2 functions. These results reveal an evolutionarily conserved role of vertebrate Nrf2 in protection against oxidative stress. Interestingly, there were no significant differences between wild-type and nrf2(fh318) larvae with regard to their sensitivity to superoxide and singlet oxygen generators, suggesting that the importance of Nrf2 in oxidative stress protection varies based on the type of reactive oxygen species (ROS).