The role of Keap1-Nrf2 system in oxidative stress response of pancreatic β-cells

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Nrf2 (NF-E2-related factor 2)is a basic region-leucine zipper-type transcription factor, which belongs to the Cap' n' collar family. Nrf2 is activated by various stresses including electrophiles, reactive oxygen species (ROS), reactive nitrogen species (RNS), and heavy metals, and coordinately induces anti-oxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1)is an adaptor protein for Cullin3-base ubiquitin E3 ligase and acts as a sensor for stresses, which strictly regulates the Nrf2 activity.We found that both Nrf2 and Keap1 are expressed in isolated islets from mice, and expression of Nrf2-target genes is upregulated by electrophiles, ROS and RNS. In addition, theβ-cell-damaged diabetes model mice crossed with Nrf2 hetero knockout showed elevated blood glucose levels and smaller islet size. Thus, these results support our contention that the Keap1-Nrf2 system plays important roles in the maintenance of pancreatic β-cells. The results further suggest that the Keap1-Nrf2 system may be involved in the pathogenesis of diabetes mellitus in stress conditions.