Megalin, proton pump inhibitors and the renin–angiotensin system in healthy and pre-eclamptic placentas

Yuan Sun, Lunbo Tan, Rugina I. Neuman, Michelle Broekhuizen, Sam Schoenmakers, Xifeng Lu, A. H. Jan Danser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Article number7407
JournalInternational Journal of Molecular Sciences
Volume22
Issue number14
DOIs
Publication statusPublished - 2 Jul 2021

Bibliographical note

Funding Information:
Funding: This research was funded by the National Natural Science Foundation of China (grant nrs. 81800383 and 81870605), Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis (ZDSYS20190902092903237), and Shenzhen Municipal Science and Technology Innovation Council (grant no. JCYJ20170817093928508 and JCYJ20190808170401660).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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