title: NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction.
abstract: During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A.
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile adobierzewska@uandes.cl.
authors.forename: Aneta
authors.initials: A
authors.lastname: Dobierzewska
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Palominos
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Irarrazabal
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Marianela
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: Laboratory of Molecular Physiology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Lozano
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Perez-Sepulveda
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Monteiro
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Yara
authors.initials: Y
authors.lastname: Burmeister
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Horacio
authors.initials: H
authors.lastname: Figueroa-Diesel
authors.affiliation: Centre for Clinical Diagnostics, Royal Brisbane and Women's Hospital, University of Queensland Centre for Clinical Research, Herston, Queensland, Australia.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Rice
authors.affiliation: Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile Department of Maternal-Fetal Medicine, Clinica Davila, Santiago, Chile.
authors.forename: Sebastian E
authors.initials: SE
authors.lastname: Illanes
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D010929:Placentation / Q000502:physiology; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011817:Rabbits; D014327:Trophoblasts / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050778:NFATC Transcription Factors
keywords: IUGR; NFAT5; placental hypoxia; placental ischemia; preeclampsia; pregnancy