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

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 b-cell damage remain elusive. To demonstrate the roles of Nrf2 in pancreatic b-cells, we used four genetically engineered mouse models: 1) b-cell–specific Keap1conditional knockout mice, 2) b-cell–specific Nos2 transgenic mice, 3) conventional Nrf2-heterozygous knockout mice, and 4) b-cell–specific Nrf2conditional 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 b-cells in the context of reactive species (RS) damage. Consistently, Nrf2 suppressed accumulation of intracellular RS in isolated islets and pancreatic b-cell lines and also decreased nitrotyrosine levels. Nrf2 induced glutathione-related genes and reduced pancreatic b-cell apoptosis mediated by nitric oxide. In contrast, Nrf2 depletion in Nrf2-heterozygous knockout and b-cell–specific Nrf2-conditional knockout mice strongly aggravated pancreatic b-cell damage. These results demonstrate that Nrf2 induction prevents RS damage in pancreatic b-cells and that the Keap1-Nrf2 system is the crucial defense pathway for the physiological and pathological protection of pancreatic b-cells. Diabetes 2014;63:605–618 | DOI: 10.2337/db13-0909