题名：Nrf2 Protects Pancreatic beta-Cells from Oxidative and Nitrosative Stress in Diabetic Model Mice.
作者：YAGISHITA Y; FUKUTOMI T; SUGAWARA A; KAWAMURA H; TAKAHASHI T; PI J; URUNO A; YAMAMOTO M;
来源：Diabetes. 2013 Nov 1. [ IF= 7.89 ] ]
摘要：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 utilized four genetically engineered
mouse models: i) beta-cell-specific Keap1-conditional knockout mice, ii)
beta-cell-specific Nos2 transgenic mice, iii) conventional Nrf2-heterozygous
knockout mice, and iv) 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 under 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 GSH-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 pancreatic beta-cells from
RS damage and the Keap1-Nrf2 system is the crucial defense pathway for the
physiological and pathological protection of pancreatic beta-cells.