Cleavage of the soluble (pro)renin receptor (sATP6AP2) in the placenta.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8006349 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-3102 (Electronic) Linking ISSN: 01434004 NLM ISO Abbreviation: Placenta Subsets: MEDLINE
    • Publication Information:
      Publication: <2010- > : Amsterdam : Elsevier
      Original Publication: London W.B. Saunders.
    • Subject Terms:
      Furin/*metabolism ; Proprotein Convertases/*metabolism ; Receptors, Cell Surface/*metabolism ; Serine Endopeptidases/*metabolism ; Trophoblasts/*metabolism ; Vacuolar Proton-Translocating ATPases/*metabolism; Humans ; Primary Cell Culture
    • Abstract:
      Introduction: The (pro)renin receptor (ATP6AP2) is cleaved and released as soluble ATP6AP2 (sATP6AP2). The sATP6AP2 is detected in plasma and urine and is elevated in women with gestational diabetes and preeclampsia. The source and cleavage pathway of sATP6AP2 in pregnancy is unknown. The syncytiotrophoblast is the major placental secretory layer and is in direct contact with maternal blood. Both FURIN and Site 1 protease (MBTPS1) cleave sATP6AP2 in non-placental cells. We postulated that ATP6AP2 was cleaved by FURIN and/or MBTPS1 and that sATP6AP2 is secreted by the placental syncytiotrophoblast.
      Methods: Term primary trophoblast cells were transfected with FURIN siRNA, negative control siRNA or vehicle. In a separate experiment, primary trophoblasts were treated with a pro-protein convertase inhibitor (DEC-RVKR-CMK), an MBTPS1 inhibitor (PF 429242) or vehicle. Trophoblasts were left to spontaneously syncytialise before cells and supernatants were collected and intracellular and extracellular sATP6AP2 levels analysed by immunoblot.
      Results: sATP6AP2 is secreted by placental trophoblasts. Levels of intra and extra-cellular sATP6AP2 decrease with syncytialisation (P = 0.01 and P = 0.02, respectively), as do FURIN mRNA (P = 0.0003) and protein (P = 0.0007). FURIN siRNA decreased FURIN mRNA and protein levels (both P < 0.0001). Neither FURIN siRNA or PF 429242 affected sATP6AP2 levels. DEC-RVKR-CMK significantly decreased extracellular sATP6AP2 protein levels (P = 0.02).
      Discussion: Soluble ATP6AP2 is secreted by placental trophoblasts and levels decrease with syncytialisation. DEC-RVKR-CMK, a broad inhibitor of pro-protein convertases reduced extracellular sATP6AP2 levels, but FURIN siRNA and MBTPS1 inhibition had no effect. Hence, a convertase other than FURIN or MBTPS1 is most likely responsible for placental sATP6AP2 secretion.
      (Copyright © 2020 Elsevier Ltd. All rights reserved.)
    • Contributed Indexing:
      Keywords: Furin; Placenta; Site 1 protease; Soluble (pro)renin receptor; Syncytiotrophoblast
    • Accession Number:
      0 (ATP6AP2 protein, human)
      0 (Receptors, Cell Surface)
      EC 3.4.21.- (Proprotein Convertases)
      EC 3.4.21.- (Serine Endopeptidases)
      EC 3.4.21.112 (membrane-bound transcription factor peptidase, site 1)
      EC 3.4.21.75 (FURIN protein, human)
      EC 3.4.21.75 (Furin)
      EC 3.6.1.- (Vacuolar Proton-Translocating ATPases)
    • Publication Date:
      Date Created: 20200913 Date Completed: 20211020 Latest Revision: 20211020
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.placenta.2020.08.019
    • Accession Number:
      32920451