Abstract
Soluble Fms-like tyrosine kinase-1 (sFlt-1) is increased in pre-eclampsia. The proton pump inhibitor (PPI) lowers sFlt-1, while angiotensin increases it. To investigate whether PPIs lower sFlt-1 by suppressing placental renin–angiotensin system (RAS) activity, we studied gene expression and protein abundance of RAS components, including megalin, a novel endocytic receptor for prorenin and renin, in placental tissue obtained from healthy pregnant women and women with early-onset pre-eclampsia. Renin, ACE, ACE2, and the angiotensin receptors were expressed at identical levels in healthy and pre-eclamptic placentas, while both the (pro)renin receptor and megalin were increased in the latter. Placental prorenin levels were upregulated in pre-eclamptic pregnancies. Angiotensinogen protein, but not mRNA, was detectable in placental tissue, implying that it originates from maternal blood. Ex vivo placental perfusion revealed a complete washout of angiotensinogen, while prorenin release remained constant. The PPI esomeprazole dose-dependently reduced megalin/(pro)renin receptor-mediated renin uptake in Brown Norway yolk sac epithelial cells and decreased sFlt-1 secretion from placental villous explants. Megalin inhibition blocked angiotensinogen uptake in epithelial cells. In conclusion, our data suggest that placental RAS activity depends on angiotensinogen taken up from the maternal systemic circulation. PPIs might interfere with placental (pro)renin-AGT uptake/transport, thereby reducing angiotensin formation as well as angiotensin-induced sFlt-1 synthesis.
Highlights
Pre-eclampsia is a hypertensive disorder characterized by new-onset hypertension and proteinuria occurring after 20 weeks of gestation
We focused on early-onset pre-eclampsia (EoPE), and not late-onset pre-eclampsia, since the latter has a different pathophysiological mechanism, being more a maternal rather than a placental syndrome, and showing clear histopathological differences
It is believed that it may contribute to pre-eclampsia, its exact role is still unknown
Summary
Pre-eclampsia is a hypertensive disorder characterized by new-onset hypertension and proteinuria occurring after 20 weeks of gestation. The plasma renin concentration rises modestly [6], and together with the rise in AGT, this results in a significant rise in plasma renin activity (PRA); ensuring sufficient RAS activity to allow water and salt retention [7,8]. Plasma prorenin levels increase much more strongly than plasma renin levels [6,9], due to prorenin release from the ovaries and, to a lesser degree, the placenta [10]. The function of this prorenin remains unclear
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