Mukaigasa, K., Nguyen, L.T., Li, L., Nakajima, H., Yamamoto, M., and Kobayashi, M. (2012) Genetic Evidence of an Evolutionarily Conserved Role for Nrf2 in the Protection against Oxidative Stress. Molecular and cellular biology. 32(21):4455-4461.
Transcription factor Nrf2 is considered to be a master regulator of antioxidant defense in mammals. However, it is unclear
whether this concept is applicable to non-mammalian vertebrates, because no animal model other than Nrf2-knockout mice has
been generated to examine the effects of Nrf2 deficiency. We herein characterize a recessive loss-of-function mutant of Nrf2
(nrf2fh318) in a lower vertebrate, the zebrafish (Danio rerio). In keeping with the findings in the mouse, nrf2fh318 mutants exhibited reduced induction of the Nrf2 target genes in response to oxidative stress and electrophiles, but were
viable and fertile, and its embryos developed normally. The nrf2fh318 larvae displayed enhanced sensitivity to oxidative stress and electrophiles, especially peroxides, and pretreatment with
an Nrf2-activating compound, sulforaphane, could decrease the peroxide-induced lethality of wild-type but not nrf2fh318 mutants, thus indicating that resistance to oxidative stress is highly dependent on Nrf2 functions. These results reveal
an evolutionarily conserved role of vertebrate Nrf2 in the protection against oxidative stress. Interestingly, there were
no significant differences between wild-type and nrf2fh318 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).