DJ-1 upregulates the Nrf2/GPX4 signal pathway to inhibit trophoblast ferroptosis in the pathogenesis of preeclampsia

Sci Rep. 2022 Feb 21;12(1):2934. doi: 10.1038/s41598-022-07065-y.

Abstract

Ferroptosis is a newly discovered mode of cell death that involves disorders in iron metabolism and the accumulation of reactive oxygen species (ROS) in the plasma membrane. Preeclampsia (PE) is a gestational idiopathic disease that is characterized by hypertension and albuminuria, begins after 20 weeks of pregnancy. DJ-1 is a prerequisite for activating and stabilizing Nrf2 to allow translocation to the nucleus to carry out further functions. Detecting the expression levels of DJ-1, the Nrf2/GPX4 signaling pathway and ferroptosis markers in placental tissues of pregnant women with and without PE. Analyzing the effects of the ferroptosis inducer (RSL3) and the inhibitor (Fer-1) on the mortality rate of BeWo cells and DJ-1+/+, DJ-1-/- BeWo cells. Ferroptosis markers (MDA concentration and morphology of trophoblast cells) and DJ-1 and its downstream the Nrf2/GPX4 signaling pathway increased significantly in PE pathological state. The expression levels of DJ-1 protein in the control group and the PE group were positively correlated with the expression levels of Nrf2/GPX4 signaling pathway protein, and negatively correlated with the MDA concentration. BeWo cells were sensitive to the ferroptosis inducer (RSL3) and the inhibitor (Fer-1). The high expression levels of DJ-1 in BeWo cells can resist ferroptosis by regulating the Nrf2/GPX4 signaling pathway. Ferroptosis is involved in the pathogenesis of PE. DJ-1 can mediate the trophoblast cells ferroptosis and play a protective role in the pathogenesis of preeclampsia by regulating the Nrf2/GPX4 signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Female
  • Ferroptosis / genetics*
  • Ferroptosis / physiology*
  • Gene Expression / genetics
  • Gene Expression Regulation / genetics
  • Humans
  • NF-E2-Related Factor 2 / metabolism*
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism*
  • Placenta / cytology
  • Pre-Eclampsia / etiology*
  • Pre-Eclampsia / genetics*
  • Pregnancy
  • Protein Deglycase DJ-1 / genetics*
  • Protein Deglycase DJ-1 / metabolism
  • Protein Deglycase DJ-1 / physiology*
  • Signal Transduction / genetics*
  • Signal Transduction / physiology*
  • Trophoblasts / physiology*
  • Up-Regulation / genetics*

Substances

  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • PARK7 protein, human
  • Protein Deglycase DJ-1