Nrf2 Protects Pancreatic β-Cells From Oxidative and Nitrosative Stress in Diabetic Model Mice

  1. Masayuki Yamamoto1,7
  1. 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
  2. 2Division of Oral and Maxillofacial Surgery, Tohoku University Graduate School of Dentistry, Sendai, Japan
  3. 3Organ Transplantation, Reconstruction, and Endoscopic Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
  4. 4Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan
  5. 5Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC
  6. 6Bioscience for Drug Discovery, Tohoku University Graduate School of Medicine, Sendai, Japan
  7. 7Tohoku Medical-Megabank Organization, Tohoku University, Sendai, Japan
  1. Corresponding authors: Masayuki Yamamoto, masiyamamoto{at}med.tohoku.ac.jp, and Akira Uruno, uruno{at}med.tohoku.ac.jp.

Abstract

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.

Footnotes

  • Received June 10, 2013.
  • Accepted October 24, 2013.

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  1. Diabetes vol. 63 no. 2 605-618
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