Preeclampsia affects 3-5% of all pregnancies and is characterised by new-onset hypertension in conjunction with gross endothelial dysfunction. In preeclamptic women, plasma levels of soluble (pro)renin receptor (s(P)RR) are elevated compared with normotensive pregnancy. We have recently shown that recombinant s(P)RR produces both endothelial dysfunction in vitro, and renal arterial dysfunction and hypertension in pregnant rats. Hence, this study aimed to assess the effects of PRO20, an s(P)RR antagonist, in ameliorating s(P)RR-induced endothelial dysfunction.
Human uterine microvascular endothelial cells (HUtMECs, n=4) were incubated for 24h with either; vehicle, 100nM recombinant s(P)RR, or 10% pooled patient serum (from normotensive or preeclamptic pregnancy, n=7) with or without 10nM PRO20. Markers of endothelial dysfunction were assessed via immunoblot, qPCR, and ELISA.
HUtMECs treated with recombinant s(P)RR displayed increased expression of endothelial dysfunction makers including vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and endothelin-1 mRNA expression (P=0.003, P=0.001, P=0.009 respectively), along with elevated endothelin-1 protein secretion (P<0.001) compared with controls. The s(P)RR-induced increase in ICAM-1 mRNA (P=0.020) and endothelin-1 mRNA and protein levels (P=0.019 and P=0.032) were mitigated by treatment with PRO20. However, VCAM-1 mRNA levels were unchanged with PRO20 treatment compared with controls.
HUtMECs cultured with preeclamptic patient serum produced similar increases in the expression of endothelial dysfunction markers VCAM-1, ICAM-1, and endothelin 1 mRNA levels (P=0.004, P=0.004, and P=0.001, respectively) and endothelin-1 protein levels (P<0.001) compared with normotensive controls. Treatment with PRO20 was unable to mitigate the preeclamptic serum-induced increase in of VCAM-1, ICAM-1, or endothelin-1 mRNA but it did restore endothelin-1 protein levels (P=0.003).
Our data shows that marked endothelial dysfunction induced by recombinant s(P)RR in vitro can be resolved by inhibiting s(P)RR using PRO20. Future studies assessing the efficacy of PRO20 treatment in vivo are necessary to explore whether inhibiting s(P)RR could be a potential therapeutic for preeclampsia.