| First Author | Yang B | Year | 2012 |
| Journal | Toxicol Appl Pharmacol | Volume | 264 |
| Issue | 3 | Pages | 315-23 |
| PubMed ID | 23000044 | Mgi Jnum | J:188999 |
| Mgi Id | MGI:5444049 | Doi | 10.1016/j.taap.2012.09.012 |
| Citation | Yang B, et al. (2012) Deficiency in the nuclear factor E2-related factor 2 renders pancreatic beta-cells vulnerable to arsenic-induced cell damage. Toxicol Appl Pharmacol 264(3):315-23 |
| abstractText | Chronic human exposure to inorganic arsenic (iAs), a potent environmental oxidative stressor, is associated with increased prevalence of type 2 diabetes, where impairment of pancreatic beta-cell function is a key pathogenic factor. Nuclear factor E2-related factor 2 (Nrf2) is a central transcription factor regulating cellular adaptive response to oxidative stress. However, persistent activation of Nrf2 in response to chronic oxidative stress, including inorganic arsenite (iAs(3+)) exposure, blunts glucose-triggered reactive oxygen species (ROS) signaling and impairs glucose-stimulated insulin secretion (GSIS). In the current study, we found that MIN6 pancreatic beta-cells with stable knockdown of Nrf2 (Nrf2-KD) by lentiviral shRNA and pancreatic islets isolated from Nrf2-knockout (Nrf2-/-) mice exhibited reduced expression of several antioxidant and detoxification enzymes in response to acute iAs(3+) exposure. As a result, Nrf2-KD MIN6 cells and Nrf2-/- islets were more susceptible to iAs(3+) and monomethylarsonous acid (MMA(3+))-induced cell damage, as measured by decreased cell viability, augmented apoptosis and morphological change. Pretreatment of MIN6 cells with Nrf2 activator tert-butylhydroquinone protected the cells from iAs(3+)-induced cell damage in an Nrf2-dependent fashion. In contrast, antioxidant N-acetyl cysteine protected Nrf2-KD MIN6 cells against acute cytotoxicity of iAs(3+). The present study demonstrates that Nrf2-mediated antioxidant response is critical in the pancreatic beta-cell defense mechanism against acute cytotoxicity by arsenic. The findings here, combined with our previous results on the inhibitory effect of antioxidants on ROS signaling and GSIS, suggest that Nrf2 plays paradoxical roles in pancreatic beta-cell dysfunction induced by environmental arsenic exposure. |
