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).

译文

:转录因子Nrf2被认为是哺乳动物抗氧化防御的主要调节剂。但是,尚不清楚该概念是否适用于非哺乳动物的脊椎动物,因为除Nrf2基因敲除小鼠以外,没有其他动物模型可以用来研究Nrf2缺乏症的影响。在这里,我们表征了低等脊椎动物斑马鱼(Danio rerio)中Nrf2(nrf2(fh318))的隐性功能丧失突变体。与小鼠模型中的发现一致,nrf2(fh318)突变体表现出对Nrf2靶基因的诱导减少,以响应氧化应激和亲电试剂,但它们具有活力和繁殖力,并且它们的胚胎正常发育。 nrf2(fh318)幼虫显示出对氧化应激和亲电子试剂(特别是过氧化物)的敏感性增强,并且在野生型中用Nrf2活化化合物萝卜硫烷进行预处理可降低过氧化物诱导的致死性,但不会降低nrf2(fh318)突变体,表明对氧化应激高度依赖于Nrf2功能。这些结果揭示了脊椎动物Nrf2在保护抗氧化应激方面的进化保守作用。有趣的是,野生型和nrf2(fh318)幼虫对超氧化物和单线态氧产生剂的敏感性之间没有显着差异,这表明Nrf2在氧化应激保护中的重要性根据活性氧种类(ROS)的不同而不同。 )。

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