Peroxidasin is a novel target of the redox-sensitive transcription factor Nrf2

Abstract

Peroxidasin (PXDN) facilitates peroxidative reactions via utilisation of hydrogen peroxide (H₂O₂) and has been shown to crosslink collagen IV through sulfilimine bond formation in the presence of hypohalous acids. Aberrant PXDN expression has been associated with kidney fibrosis, cancer, congenital eye defects and various cardiovascular disorders. Since PXDN expression is modified by H₂O₂, we hypothesized that a major antioxidant response transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), may regulate PXDN expression. PXDN expression in response to H₂O₂ and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells. Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the regulation of PXDN by Nrf2. We observed elevated Nrf2 nuclear translocation and increased PXDN protein expression in response to H₂O₂, tBHQ and SFN, in both cell lines. We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. This finding further highlights the role of PXDN in redox-related processes and compliments the currently understood pathophysiological functions of PXDN.

Keywords: Cancer; Cardiovascular; Fibrosis; Peroxidase; VPO1; Wound healing.