| First Author | Yagishita Y | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 2 | Pages | 605-18 |
| PubMed ID | 24186865 | Mgi Jnum | J:209004 |
| Mgi Id | MGI:5565542 | Doi | 10.2337/db13-0909 |
| Citation | Yagishita Y, et al. (2014) Nrf2 protects pancreatic beta-cells from oxidative and nitrosative stress in diabetic model mice. Diabetes 63(2):605-18 |
| abstractText | 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 beta-cell damage remain elusive. To demonstrate the roles of Nrf2 in pancreatic beta-cells, we used four genetically engineered mouse models: 1) beta-cell-specific Keap1-conditional knockout mice, 2) beta-cell-specific Nos2 transgenic mice, 3) conventional Nrf2-heterozygous knockout mice, and 4) beta-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 beta-cells in the context of reactive species (RS) damage. Consistently, Nrf2 suppressed accumulation of intracellular RS in isolated islets and pancreatic beta-cell lines and also decreased nitrotyrosine levels. Nrf2 induced glutathione-related genes and reduced pancreatic beta-cell apoptosis mediated by nitric oxide. In contrast, Nrf2 depletion in Nrf2-heterozygous knockout and beta-cell-specific Nrf2-conditional knockout mice strongly aggravated pancreatic beta-cell damage. These results demonstrate that Nrf2 induction prevents RS damage in pancreatic beta-cells and that the Keap1-Nrf2 system is the crucial defense pathway for the physiological and pathological protection of pancreatic beta-cells. |
