title: Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage.
abstract: Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic β-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs³⁺) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic β-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2⁻/⁻) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs³⁺ exposure. As a result, Nrf2-KD MIN6 cells and Nrf2⁻/⁻ islets were more susceptible to iAs³⁺ and monomethylarsonous acid (MMA³⁺)-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs³⁺-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N-acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs³⁺. The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic β-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic β-cell dysfunction induced by environmental arsenic exposure.
authors.affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Bei
authors.initials: B
authors.lastname: Yang
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zheng
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Kathy
authors.initials: K
authors.lastname: Yarborough
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D000818:Animals; D000975:Antioxidants; D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D004785:Environmental Pollutants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D001151:Arsenic