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

Abstract

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.

Keywords: Apoptosis; H(2)O(2); KEAP1; NRF2; Pancreatic β-cell.