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

• Published in: Diabetes (New York, N.Y.) Vol. 63; no. 2; pp. 605 - 618
• Main Authors: Yagishita, Yoko, Fukutomi, Toshiaki, Sugawara, Akira, Kawamura, Hiroshi, Takahashi, Tetsu, Pi, Jingbo, Uruno, Akira, Yamamoto, Masayuki
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2014
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aging; Animals; Biological and medical sciences; Blood Glucose; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Diabetes; Diabetes Mellitus - genetics; Diabetes Mellitus - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation - physiology; Genetic aspects; Imidazoles; Insulin - genetics; Insulin - metabolism; Insulin-Secreting Cells - metabolism; Kelch-Like ECH-Associated Protein 1; Medical sciences; Mice; Mice, Knockout; Mice, Transgenic; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitrogen in the body; Oleanolic Acid - analogs & derivatives; Oxidative Stress; Pancreatic beta cells; Physiological aspects; Promoter Regions, Genetic; Rats; Transcription factors; Endocrinopathy; Animal model; Vertebrata; Mammalia; Mouse; Animal; Diabetes mellitus; Langerhans islet; Rodentia; β Cell; Stress; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db13-0909

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.