Molecular hydrogen ameliorates several characteristics of preeclampsia in the Reduced Uterine Perfusion Pressure (RUPP) rat model

Free Radic Biol Med. 2016 Dec:101:524-533. doi: 10.1016/j.freeradbiomed.2016.10.491. Epub 2016 Oct 24.


Oxidative stress plays an important role in the pathogenesis of preeclampsia. Recently, molecular hydrogen (H2) has been shown to have therapeutic potential in various oxidative stress-related diseases. The aim of this study is to investigate the effect of H2 on preeclampsia. We used the reduced utero-placental perfusion pressure (RUPP) rat model, which has been widely used as a model of preeclampsia. H2 water (HW) was administered orally ad libitum in RUPP rats from gestational day (GD) 12-19, starting 2 days before RUPP procedure. On GD19, mean arterial pressure (MAP) was measured, and samples were collected. Maternal administration of HW significantly decreased MAP, and increased fetal and placental weight in RUPP rats. The increased levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and diacron reactive oxygen metabolites as a biomarker of reactive oxygen species in maternal blood were decreased by HW administration. However, vascular endothelial growth factor level in maternal blood was increased by HW administration. Proteinuria, and histological findings in kidney were improved by HW administration. In addition, the effects of H2 on placental villi were examined by using a trophoblast cell line (BeWo) and villous explants from the placental tissue of women with or without preeclampsia. H2 significantly attenuated hydrogen peroxide-induced sFlt-1 expression, but could not reduce the expression induced by hypoxia in BeWo cells. H2 significantly attenuated sFlt-1 expression in villous explants from women with preeclampsia, but not affected them from normotensive pregnancy. The prophylactic administration of H2 attenuated placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress. These results support the theory that H2 has a potential benefit in the prevention of preeclampsia.

Keywords: Angiogenic factors; Antioxidants; Hydrogen peroxide; Molecular hydrogen; Oxidative stress; Preeclampsia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Disease Models, Animal
  • Female
  • Fetus
  • Gene Expression Regulation
  • Gestational Age
  • Humans
  • Hydrogen / pharmacology*
  • Organ Size / drug effects
  • Placenta / blood supply
  • Placenta / drug effects
  • Placenta / metabolism
  • Pre-Eclampsia / drug therapy*
  • Pre-Eclampsia / genetics
  • Pre-Eclampsia / metabolism
  • Pre-Eclampsia / pathology
  • Pregnancy
  • Proteinuria / drug therapy*
  • Proteinuria / genetics
  • Proteinuria / metabolism
  • Proteinuria / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / antagonists & inhibitors*
  • Reactive Oxygen Species / metabolism
  • Uterus / blood supply
  • Uterus / drug effects
  • Uterus / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism


  • Reactive Oxygen Species
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Hydrogen
  • Flt1 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-1