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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 (iAs{sup 3+}) 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 iAs{sup 3+} exposure. As a result, Nrf2-KD MIN6 cells and Nrf2−/− islets were more susceptible to iAs{sup 3+} and monomethylarsonous acid (MMA{sup 3+})-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 iAs{sup 3+}-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N‐acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs{sup 3+}. The present study demonstrates that Nrf2-mediated antioxidant response ismore » 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. -- Highlights: ► Lack of Nrf2 reduced expression of antioxidant genes induced by iAs{sup 3+} in β-cells. ► Deficiency of Nrf2 in β-cells sensitized to iAs{sup 3+} and MMA{sup 3+}-induced cytotoxicity. ► Nrf2 activation protected β-cells from acute iAs{sup 3+} cytotoxicity.« less

Authors:
 [1];  [2]; ; ; ; ; ; ; ;  [1];  [1]
  1. Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States)
  2. (China)
Publication Date:
OSTI Identifier:
22215951
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 264; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; APOPTOSIS; ARSENIC; BENZOQUINONES; CATTLE; CYSTEINE; DETOXIFICATION; GLUCOSE; HEME; INSULIN; IODIDES; KNOCK-OUT REACTIONS; LIGASES; MICE; MORPHOLOGICAL CHANGES; NAD; OXIDATION; OXYGEN; PANCREAS; PHOSPHATES; RIBOSOMAL RNA; SECRETION; TOXICITY; TRANSCRIPTION FACTORS

Citation Formats

Yang, Bei, Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang 110001, Fu, Jingqi, Zheng, Hongzhi, Xue, Peng, Yarborough, Kathy, Woods, Courtney G., Hou, Yongyong, Zhang, Qiang, Andersen, Melvin E., and Pi, Jingbo, E-mail: jpi@thehamner.org. Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.09.012.
Yang, Bei, Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang 110001, Fu, Jingqi, Zheng, Hongzhi, Xue, Peng, Yarborough, Kathy, Woods, Courtney G., Hou, Yongyong, Zhang, Qiang, Andersen, Melvin E., & Pi, Jingbo, E-mail: jpi@thehamner.org. Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage. United States. doi:10.1016/J.TAAP.2012.09.012.
Yang, Bei, Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang 110001, Fu, Jingqi, Zheng, Hongzhi, Xue, Peng, Yarborough, Kathy, Woods, Courtney G., Hou, Yongyong, Zhang, Qiang, Andersen, Melvin E., and Pi, Jingbo, E-mail: jpi@thehamner.org. Thu . "Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage". United States. doi:10.1016/J.TAAP.2012.09.012.
@article{osti_22215951,
title = {Deficiency in the nuclear factor E2-related factor 2 renders pancreatic β-cells vulnerable to arsenic-induced cell damage},
author = {Yang, Bei and Department of Histology and Embryology, College of Basic Medical Sciences, China Medical University, Shenyang 110001 and Fu, Jingqi and Zheng, Hongzhi and Xue, Peng and Yarborough, Kathy and Woods, Courtney G. and Hou, Yongyong and Zhang, Qiang and Andersen, Melvin E. and Pi, Jingbo, E-mail: jpi@thehamner.org},
abstractNote = {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 (iAs{sup 3+}) 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 iAs{sup 3+} exposure. As a result, Nrf2-KD MIN6 cells and Nrf2−/− islets were more susceptible to iAs{sup 3+} and monomethylarsonous acid (MMA{sup 3+})-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 iAs{sup 3+}-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N‐acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs{sup 3+}. 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. -- Highlights: ► Lack of Nrf2 reduced expression of antioxidant genes induced by iAs{sup 3+} in β-cells. ► Deficiency of Nrf2 in β-cells sensitized to iAs{sup 3+} and MMA{sup 3+}-induced cytotoxicity. ► Nrf2 activation protected β-cells from acute iAs{sup 3+} cytotoxicity.},
doi = {10.1016/J.TAAP.2012.09.012},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 264,
place = {United States},
year = {2012},
month = {11}
}