title: Chronic tempol prevents hypertension, proteinuria, and poor feto-placental outcomes in BPH/5 mouse model of preeclampsia.
abstract: Recently we described a mouse model, BPH/5, that spontaneously develops the hallmark clinical features of preeclampsia. BPH/5 exhibit impaired placentation before the onset of hypertension and proteinuria, supporting a causal role for the placenta in the pathogenesis of preeclampsia. Here we tested the hypothesis that an increase in reactive oxygen species (ROS) early in pregnancy results in placental abnormalities leading to the maternal symptoms of preeclampsia. We further hypothesized that chronic antioxidant therapy would ameliorate both feto-placental abnormalities and maternal symptoms. ROS levels measured by dihydroethidium revealed significant increases in oxidative stress in BPH/5 placentas at midgestation compared with C57 controls. This increase in ROS was correlated with reduced expression and activity of cytoplasmic superoxide dismutase in early and midgestation BPH/5 placentas. These abnormalities in placental oxidant factors occurred before the onset of maternal symptoms, suggesting a possible causal link between increased ROS and maternal and feto-placental pathology in this model. In support of this, chronic treatment of BPH/5 with the superoxide dismutase-mimetic Tempol throughout gestation significantly improved fetal growth and survival. Furthermore, Tempol ameliorated pregnancy-induced increases in blood pressure and proteinuria in BPH/5 mothers. We confirmed that Tempol radical was present in plasma, and it normalized ROS levels in all placental zones in BPH/5. These data for the first time demonstrate an important causative role for increased ROS in the placenta in the pathogenesis of preeclampsia in a model that spontaneously develops the disease. The results also strongly suggest the potential utility of antioxidant therapy in treating preeclampsia.
authors.affiliation: Department of Anatomy and Cell Biology, the University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, USA.
authors.forename: Darren S
authors.initials: DS
authors.lastname: Hoffmann
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Weydert
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
authors.forename: William J
authors.initials: WJ
authors.lastname: Kutschke
authors.forename: Martha F
authors.initials: MF
authors.lastname: Kienzle
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Leach
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Sharma
authors.forename: Ram V
authors.initials: RV
authors.lastname: Sharma
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000517:prevention & control*; D006977:Hypertension, Renal / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D010920:Placenta / Q000187:drug effects / Q000378:metabolism; D011225:Pre-Eclampsia / Q000188:drug therapy*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011507:Proteinuria / Q000517:prevention & control*; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D013481:Superoxides; D013482:Superoxide Dismutase; C001803:tempol