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Published on: January 26, 2024
L-Citrulline Improves IGF-1 Signaling Pathway in Preeclampsia via Polyamines
Andy W C Man1, Joscha Steetskamp2, Josche van der Ven2
1Department of Pharmacology (A.W.C.M., G.R., N.X., H.L.), Cardiology I, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Insights
L-citrulline supplementation may treat preeclampsia by enhancing insulin-like growth factor 1 (IGF-1) signaling, partly through polyamine production. This offers a potential therapeutic strategy for this severe pregnancy complication.
Area of Science:
- Obstetrics and Gynecology
- Molecular Medicine
- Nutritional Science
Background:
- Preeclampsia is a severe pregnancy complication lacking effective pharmacological treatments.
- Previous studies showed L-citrulline improves preeclampsia in a rat model.
- This study investigates the molecular mechanisms of L-citrulline's effects.
Purpose of the Study:
- To elucidate the molecular mechanisms by which L-citrulline supplementation impacts preeclampsia.
- To investigate the role of IGF-1 signaling and polyamine metabolism in preeclampsia.
- To explore L-citrulline as a potential therapeutic agent for preeclampsia.
Main Methods:
- Treatment of pregnant Dahl salt-sensitive rats with L-citrulline.
- Recruitment of preeclampsia patients for placental and serum sample collection.
- Analysis of placental gene expression (IGF-1, ZEB1, miR-486-5p, miR-210) and serum polyamine levels.
Main Results:
- Preeclamptic placentas showed reduced IGF-1, ZEB1, and increased miR-486-5p, miR-210.
- L-citrulline treatment in rats normalized these placental markers and maintained serum polyamine levels.
- L-citrulline and polyamines improved IGF-1 expression in cultured cells, with effects partly dependent on IGF-1.
Conclusions:
- L-citrulline supplementation improves IGF-1 signaling in preeclampsia, partly via polyamine production.
- Maternal L-citrulline or polyamine supplementation may be a safe and effective therapeutic strategy for preeclampsia.
Background:
Preeclampsia is a severe pregnancy complication with no effective pharmacological therapy available. We previously demonstrated that L-citrulline supplementation improves preeclampsia phenotypes in Dahl salt-sensitive rats, an animal model of superimposed preeclampsia. This study aimed to investigate the underlying molecular mechanisms.
Methods:
Pregnant Dahl salt-sensitive rats were treated with L-citrulline. In addition, patients with preeclampsia were recruited to donate placenta and serum samples.
Results:
In patients with preeclampsia, the placental IGF-1 (insulin-like growth factor 1) expression was significantly reduced compared with healthy pregnancy, associated with a downregulation of ZEB1 (zinc finger E-box binding homeobox 1) and an upregulation of miR-486-5p and miR-210. L-citrulline supplementation in preeclampsia rats significantly increased the placental expression of IGF-1 and ZEB1 and reduced the expression of miR-486-5p and miR-210. Total serum polyamine level was reduced in patients with preeclampsia and pregnant Dahl salt-sensitive rats, while L-citrulline treatment maintained the serum polyamine level in Dahl salt-sensitive rats during pregnancy. Placental IGF-1 expression was positively correlated to serum polyamine levels. Moreover, both L-citrulline and polyamines normalized the expression of IGF-1 and some antiangiogenic markers in cultured human placental vascular endothelial cells treated with preeclampsia serum. Results from IGF-1 siRNA experiments indicate that part of the L-citrulline effects on gene expression was dependent on IGF-1.
Conclusions:
L-citrulline supplementation improves the IGF-1 signaling pathway in preeclampsia, at least partly, via polyamine production. Maternal supplementation with L-citrulline or polyamine may represent a safe and effective therapeutic strategy for preeclampsia.
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