KEAP1/NRF2 axis regulates H2O2-induced apoptosis of pancreatic β-cells

• Published in: Gene 2019-04, Vol.691, p.8-17
• Main Authors: He, Jinshui, Zhang, Xu, Lian, Chaowei, Wu, Jinzhi, Fang, Yanling, Ye, Xiaoling
• Format: Article
• Language: English
• Subjects: Apoptosis; H2O2; KEAP1; NRF2; Pancreatic β-cell
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2018.11.100

In human pancreatic β-cells, oxidative stress and cellular injures can be induced by H2O2 treatment. The KEAP1/NRF2 axis is a key antioxidant signaling pathway. The present study attempted to elucidate the mechanism by which the KEAP1/NRF2 axis mediates oxidative stress-induced death in pancreatic β-cells. Our data showed that H2O2 treatment obviously induced the apoptosis of β-cells. Further experiments demonstrated that KEAP1 expression was downregulated in H2O2-treated pancreatic β-cells and this change correlated with increase in the cellular abundance and nuclear translocation of NRF2. The restoration of KEAP1 expression in cells resulted in a recovery of cell proliferation and inhibition of apoptosis. Furthermore, we found that KEAP1 overexpression negatively regulated the abundance of NRF2, subsequently causing decreased antioxidant response element activation. This led to HO-1 protein downregulation in H2O2-treated human pancreatic β-cells, which was also observed in NRF2-silenced β-cells. Conversely, the silencing of KEAP1 led to NRF2 upregulation and inhibited ARE and HO-1 signaling in pancreatic β-cells. The increase in the abundance of NRF2 following treatment with H2O2 drastically elevated the production of BAX, FAS, FAS-L, CASP-3, and CASP-9, and this change was reversed by KEAP1 overexpression or NRF2 silencing. Taken together, H2O2 treatment activated KEAP1/NRF2 signaling to promote the production of pro-apoptotic factors and consequently led to the apoptosis of human pancreatic β-cells. •We tested the role and mechanism of KEAP1/NRF2 in pancreatic β-cells.•KEAP1 downregulation promoted apoptosis through upregulating the production of PAFs.•H2O2 treatment activated KEAP1/NRF2 signaling to promote the production of PAFs.