Dysfunction of Nrf2 decreases KBrO₃-induced oxidative DNA damage in Ogg1-null mice

Transcription factor Nrf2 regulates production of antioxidants and protects cells from oxidative/electrophilic stresses. Paradoxically, glutathione, one of the Nrf2-regulated antioxidants, has been assumed to promote genotoxicity of KBrO₃. To address this glutathione hypothesis, we examined roles Nrf2 plays in the cellular defense against KBrO₃-induced oxidative damage using Nrf2^-/-, Ogg1^-/- and Nrf2::Ogg1 double knockout mice. We found that upon KBrO₃ treatment Nrf2::Ogg1 double knockout animals suffered from severe kidney damage, but unexpectedly the double knockout mice accumulated lower level of 8-hydroxyguanine than Ogg1^-/- mice. Thus, KBrO₃-induced nephrotoxicity appears not to depend on the formation of 8-hydroxyguanine. Our data also indicate that both the KBrO₃-induced nephrotoxicity and formation of 8-hydroxyguanine are Nrf2-controlled processes, but the changes of the glutathione level are Nrf2-independent. Based on these results we conclude that glutathione is a minor part of the mechanism promoting genotoxicity of KBrO₃ in Ogg1 knockout mice.