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<p>Preeclampsia (PE) is a complex disease with unclear etiology. It is the most dangerous human pregnancy disease, causing morbidity and mortality in thousands of women and newborns worldwide. The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is currently the best and only predictive biomarker. The higher the ratio, the more likely the pregnant women will develop PE. The molecular mechanism underlying the increased sFlt-1/PlGF ratio is not known. Here, we show that amino acid transporter LAT1 (<i>SLC7A5</i>) and transcription factor NRF2 regulate this ratio via a previously unknown mechanism to produce sFlt-1 and PlGF in an anti-angiogenic ratio as observed in PE. In addition, we show that PE-associated oxidative stress, whose origin was unknown, is a secondary phenomenon caused by reduced NRF2 and LAT1 activity. The interdependence of the involved proteins, including also ATF4, Flt-1 and Akt, indicates that any disruption of the interaction would ultimately lead to a PE-like phenotype.</p>

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LAT1-NRF2 axis controls sFlt-1/PlGF imbalance and oxidative stress in preeclampsia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月14日

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  • Sebastian Granitzer,
  • Raimund Widhalm,
  • Isabella Ellinger,
  • Harald Zeisler,
  • Martin Forsthuber,
  • Philipp Foessleitner,
  • Elisabeth Geschrey,
  • Leila Saleh,
  • Martin Knöfler,
  • Gernot Desoye,
  • Paul Ettel,
  • Thomas Weichhart,
  • Laszlo Musiejovsky,
  • Gernot Schabbauer,
  • Hans Salzer,
  • Margit Rosner,
  • Markus Hengstschläger,
  • Claudia Gundacker

摘要

Preeclampsia (PE) is a complex disease with unclear etiology. It is the most dangerous human pregnancy disease, causing morbidity and mortality in thousands of women and newborns worldwide. The soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) ratio is currently the best and only predictive biomarker. The higher the ratio, the more likely the pregnant women will develop PE. The molecular mechanism underlying the increased sFlt-1/PlGF ratio is not known. Here, we show that amino acid transporter LAT1 (SLC7A5) and transcription factor NRF2 regulate this ratio via a previously unknown mechanism to produce sFlt-1 and PlGF in an anti-angiogenic ratio as observed in PE. In addition, we show that PE-associated oxidative stress, whose origin was unknown, is a secondary phenomenon caused by reduced NRF2 and LAT1 activity. The interdependence of the involved proteins, including also ATF4, Flt-1 and Akt, indicates that any disruption of the interaction would ultimately lead to a PE-like phenotype.