Gadd45a stress signaling regulates sFlt‐1 expression in preeclampsia

Abstract

Preeclampsia, which affects approximately 5-8% of all pregnancies and is one of the leading causes of maternal and fetal morbidity and mortality, is a pregnancy induced complex of multiple pathological changes, including elevated blood pressure, proteinuria and edema manifested after 20 weeks gestation. There is growing evidence that placental stresses during pregnancy, notably hypoxia, and an increase in circulating soluble Flt-1 (sFlt-1) are important in the etiopathogenesis of preeclampsia. How placental stress results in elevated sFlt-1 expression is currently unknown. Here we provide novel data implicating the Gadd45a stress sensor protein as an upstream modulator of pathophysiological changes observed in preeclampsia. It is shown that Gadd45a expression and activation of its downstream effector p38 kinase are elevated in preeclamptic placentas compared to non-preeclamptic controls, and correlate with elevated sFlt-1. Furthermore, a regulatory loop is demonstrated where stress, including hypoxia, IL-6 or hypertonic stress, caused induction of Gadd45a, leading to p38 activation and ultimately increasing sFlt-1 secretion in endothelial cells. These data provide a compelling working frame to further test the role of Gadd45 stress sensors in the etiology of preeclampsia, and set the stage for considering novel therapeutic regimens, including p38 inhibitors, for treatment of preeclampsia.

Gadd45α as an upstream signaling molecule of p38 MAPK triggers oxidative stress-induced sFlt-1 and sEng upregulation in preeclampsia

“…Although Xiong et al (2009) have demonstrated that Gadd45α expression and the activation of its downstream effector p38 kinase are elevated in preeclamptic placentas compared with non-preeclamptic controls, the subjects in the previous study were American. Therefore, a repetition of these experiments in the Chinese population should make this study more rigorous and convincing.…”

“…In order to block the p38 MAPK pathway, HUVECs were pre-incubated with 5 μM SB203580 (Invitrogen, Carlsbad, Calif., USA), a specific inhibitor of p38 MAPK, 90 min before H/R exposure as previously described (Xiong et al 2009). SB203580 was dissolved in dimethyl sulfoxide (DMSO).…”

“…However, few data are available on the potential function of Gadd45α in the process of placental oxidative stress. Xiong et al (2009) have observed that Gadd45α and phospho-p38 (p-p38) proteins are detected in endothelial cells only in preeclamptic placentas. Several studies have also confirmed that hypoxia/reoxygenation (H/R) rather than hypoxia alone can induce the apoptosis of endothelial cells (DharMascareno et al 2005;Tretyakov and Farber 1995) and intracellular reactive oxygen species (ROS) accumulation (Therade-Matharan et al 2004), which can alter cell signaling and cause damage to lipids, proteins, and DNA, leading to I/R injury (Dhar-Mascareno et al 2005).…”

“…Recently, a novel study has demonstrated that stress, including hypoxia, interleukin-6, or hypertonic stress, causes the induction of growth arrest and DNA damageinducible 45 alpha (Gadd45α), leading to p38 mitogenactivated protein kinase (MAPK) activation and ultimately to an increase of sFlt-1 secretion in endothelial cells (Xiong et al 2009). However, this elaborate mechanism remains perplexing.…”

Hypoxia-Mediated Soluble Fms-Like Tyrosine Kinase 1 Increase Is Not Attenuated in Interleukin 6-Deficient Mice

“…In Human umbilical vein endothelial cells (HUVECs), cellular stress like hypoxia or IL-6 stimulation results in Gadd45a induction, p38 activation, and subsequently leads to the increase in sFlt-1 levels. 40 Also, when stimulating pregnant mice with serum from patients with preeclampsia, Zhou et al observed an increase in placental sFlt-1 expression that was blocked by pretreatment of the animals with an IL-6 neutralizing antibody. 25 This suggests a regulatory function of IL-6 in sFlt-1 production.…”