L-Citrulline Improves IGF-1 Signaling Pathway in Preeclampsia via Polyamines

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.