title: Nrf2 protects pancreatic β-cells from oxidative and nitrosative stress in diabetic model mice.
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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yagishita
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukutomi
authors.forename: Akira
authors.initials: A
authors.lastname: Sugawara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamura
authors.forename: Tetsu
authors.initials: T
authors.lastname: Takahashi
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
authors.forename: Akira
authors.initials: A
authors.lastname: Uruno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000375:Aging; D000818:Animals; D001786:Blood Glucose; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D007093:Imidazoles; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D051381:Rats
chemical_list: C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D003598:Cytoskeletal Proteins; D007093:Imidazoles; D007328:Insulin; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009828:Oleanolic Acid; D052247:Nitric Oxide Synthase Type II