OPRK1 insufficiency results in trophoblast dysfunction and correlates with preeclampsia pathogenesis

Aberrations in trophoblast proliferation, invasion and hypoxia adaptation are implicated in pregnancy-related complications. OPRK1, encoding the κ-opioid receptor 1, is a member of the G protein-coupled receptors. In this study, we observed a marked downregulation of OPRK1 in decidual-side placental tissue from patients with preeclampsia (PE). Using HTR-8/SVneo trophoblasts, we found that OPRK1 knockdown inhibited cells migration, induced G0/G1 arrest and increased apoptosis, while overexpression reversed these effects. OPRK1 knockdown suppressed PI3K/AKT signaling and epithelial-mesenchymal-transition related pathways. In a L-NAME-induced PE mouse model, the OPRK1 agonist U50488H administration ameliorated PE-related symptoms including hypertension, placental defects, and fetal growth restriction. Therefore, our data indicated that OPRK1 may represent a potential therapeutic target for PE, although further validation in preclinical models is needed.