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NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction
Aneta Dobierzewska1, Macarena Palominos2, Carlos E Irarrazabal3
1Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile adobierzewska@uandes.cl.
Insights
Nuclear factor of activated T cells-5 (NFAT5) is activated in placental hypoxia, a key factor in preeclampsia and intrauterine growth restriction. This study identifies NFAT5 as a potential novel marker for placental hypoxia, independent of HIF1A.
Area of Science:
- Reproductive biology
- Molecular endocrinology
- Pathophysiology of pregnancy
Background:
- Persistent placental hypoxia is a critical factor in pregnancy complications like preeclampsia (PE) and intrauterine growth restriction (IUGR).
- These conditions affect maternal and fetal health, necessitating better diagnostic markers.
- Nuclear factor of activated T cells-5 (NFAT5) is known for its role in osmosensation and has recently been identified as hypoxia-inducible.
Purpose of the Study:
- To investigate the role and activation of NFAT5 in placental hypoxia associated with PE and IUGR.
- To determine if NFAT5 activation in placental hypoxia is independent of HIF1A.
- To explore NFAT5 as a potential novel biomarker for placental hypoxia.
Main Methods:
- In vitro studies using JAR cells exposed to low oxygen (1% O2).
- In vivo analysis of human PE and IUGR placentas, and a rabbit model of induced IUGR.
- Quantitative real-time PCR, Western blot analysis, and lambda protein phosphatase treatment were employed.
Main Results:
- Hypoxia induced NFAT5 mRNA and nuclear abundance in JAR cells, preceding HIF1A induction.
- NFAT5 mRNA and nuclear content were upregulated in human PE and rabbit IUGR placentas.
- NFAT5 nuclear accumulation was partly due to phosphorylation, and its known downstream targets (AR, SMIT) were not upregulated, suggesting a distinct function.
Conclusions:
- NFAT5 is activated in placental hypoxia in vitro and in vivo during PE and IUGR.
- Hypoxia-induced NFAT5 activation appears independent of HIF1A.
- NFAT5 may serve as a novel marker for placental hypoxia and ischemia.
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.
