Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity.
Arsenic is widely spread in our living environment and imposes a big challenge on human health worldwide. Arsenic damages biological systems through multiple mechanisms including the generation of reactive oxygen species. The transcription factor Nrf2 regulates the cellular antioxidant response that protects cells from various insults. In this study, the protective role of Nrf2 in arsenic toxicity was investigated in a human bladder urothelial cell line, UROtsa. Using a UROtsa cell line stably infected with Nrf2-siRNA, we clearly demonstrate that compromised Nrf2 expression sensitized the cells to As(III)- and MMA(III)-induced toxicity. On the other hand, the activation of the Nrf2 pathway by tert-butylhydroquinone (tBHQ) and sulforaphane (SF), the known Nrf2-inducers, rendered UROtsa cells more resistant to As(III) and MMA(III). Furthermore, the wild-type mouse embryo fibroblast (WT-MEF) cells were protected from As(III)- and MMA(III)-induced toxicity following Nrf2 activation by tBHQ or SF, whereas neither tBHQ nor SF conferred protection in the Nrf2(-/-)MEF cells, demonstrating that tBHQ- or SF-mediated protection against As(III)- and MMA(III)-induced toxicity depends on Nrf2 activation. These results, obtained by both loss of function and gain of function analyses, clearly demonstrate the protective role of Nrf2 in arsenic-induced toxicity. The current work lays the groundwork for using Nrf2 activators for therapeutic and dietary interventions against adverse effects of arsenic.
Wang
Xiao-Jun
XJ
Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel St., Tucson, AZ 85721, USA.
Sun
Zheng
Z
Chen
Weimin
W
Eblin
Kylee E
KE
Gandolfi
Jay A
JA
Zhang
Donna D
DD
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D001152:Arsenicals / Q000009:adverse effects*; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D017879:Isothiocyanates; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017670:Sodium Compounds / Q000633:toxicity*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D001743:Urinary Bladder / Q000166:cytology; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D001152:Arsenicals; D018053:Arsenites; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D017670:Sodium Compounds; D013454:Sulfoxides; D013861:Thiocyanates; C017947:sodium arsenite; C018855:2-tert-butylhydroquinone; C016766:sulforaphane; C020300:monomethylarsonic acid