Unravelling soluble (pro)renin receptor-mediated endothelial dysfunction

Preeclampsia is characterized by maternal endothelial dysfunction and new-onset hypertension. Preeclamptic pregnancies have elevated levels of maternal soluble prorenin receptor (s(P)RR) and previous studies have shown that recombinant s(P)RR produces hypertension and vascular dysfunction. This study aimed to investigate the effects of PRO20, an s(P)RR antagonist, on s(P)RR-induced endothelial dysfunction and its interaction with the Angiotensin II Type 1 Receptor (AT₁R).

Human uterine microvascular endothelial cells (HUtMECs) were treated with 100 nM s(P)RR, with/without 10 nM PRO20, 10 μM Losartan (AT₁R antagonist), or 10 μM Aliskerin (renin inhibitor). The ability of PRO20 to prevent endothelial dysfunction induced by patient serum from preeclamptic pregnancies was also assessed. Endothelial dysfunction markers were measured using immunoblot, qPCR, and ELISA. For AT₁R mechanism studies, HUtMECs were treated with control or AT₁R siRNA before s(P)RR exposure. AT₁R and s(P)RR protein structures were predicted via AlphaFold-2 and docking examined using Schrödinger.

PRO20 mitigated s(P)RR-induced increases in the mRNA expression of endothelial dysfunction markers, endothelin-1, VCAM-1 and ICAM-1 and prevented s(P)RR and preeclamptic serum-induced increases in endothelin-1 and VCAM-1 protein. Aliskerin had no effect on s(P)RR-induced endothelial dysfunction. Losartan and an AT₁R siRNA were able to prevent s(P)RR induced increases in VCAM-1 protein levels and ET-1 mRNA expression, respectively. Modelling suggested that PRO20 can impair s(P)RR-AT₁R complex formation.

Elevated s(P)RR induces endothelial dysfunction at least partially through AT₁R. PRO20 prevents s(P)RR-AT₁R formation, suggesting it could be an effective therapeutic for preeclampsia and conditions requiring renin-angiotensin system suppression.