Nrf2 Protects Pancreatic β-Cells From Oxidative and Nitrosative Stress in Diabetic Model Mice
- Yoko Yagishita1,2,
- Toshiaki Fukutomi1,3,
- Akira Sugawara4,
- Hiroshi Kawamura2,
- Tetsu Takahashi2,
- Jingbo Pi5,
- Akira Uruno1,6⇑ and
- Masayuki Yamamoto1,7⇑
- 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
- 2Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan
- 3Organ Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
- 4Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan
- 5Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC
- 6Bioscience for Drug Discovery, Tohoku University Graduate School of Medicine, Sendai, Japan
- 7Tohoku Medical-Megabank Organization, Tohoku University, Sendai, Japan
- Corresponding authors: Masayuki Yamamoto, , and Akira Uruno, .
Transcription factor Nrf2 (NF-E2–related factor 2) regulates wide-ranging cytoprotective genes in response to environmental stress. Keap1 (Kelch-like ECH–associated protein 1) is an adaptor protein for Cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. The Keap1-Nrf2 system plays important roles in the oxidative stress response and metabolism. However, the roles Nrf2 plays in prevention of pancreatic β-cell damage remain elusive. To demonstrate the roles of Nrf2 in pancreatic β-cells, we used four genetically engineered mouse models: 1) β-cell–specific Keap1-conditional knockout mice, 2) β-cell–specific Nos2 transgenic mice, 3) conventional Nrf2-heterozygous knockout mice, and 4) β-cell–specific Nrf2-conditional knockout mice. We found that Nrf2 induction suppressed the oxidative DNA-adduct formation in pancreatic islets of iNOS-Tg mice and strongly restored insulin secretion from pancreatic β-cells in the context of reactive species (RS) damage. Consistently, Nrf2 suppressed accumulation of intracellular RS in isolated islets and pancreatic β-cell lines and also decreased nitrotyrosine levels. Nrf2 induced glutathione-related genes and reduced pancreatic β-cell apoptosis mediated by nitric oxide. In contrast, Nrf2 depletion in Nrf2-heterozygous knockout and β-cell–specific Nrf2-conditional knockout mice strongly aggravated pancreatic β-cell damage. These results demonstrate that Nrf2 induction prevents RS damage in pancreatic β-cells and that the Keap1-Nrf2 system is the crucial defense pathway for the physiological and pathological protection of pancreatic β-cells.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0909/-/DC1.
- Received June 10, 2013.
- Accepted October 24, 2013.
- © 2014 by the American Diabetes Association.
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