title: The (pro)renin receptor mediates constitutive PLZF-independent pro-proliferative effects which are inhibited by bafilomycin but not genistein.
abstract: The (pro)renin receptor [(P)RR] is crucial for cardio-renal pathophysiology. The distinct molecular mechanisms of this receptor are still incompletely understood. The (P)RR is able to interact with different signalling proteins such as promyelocytic leukemia zinc finger protein (PLZF) and Wnt receptors. Moreover, domains of the (P)RR are essential for V-ATPase activity. V-ATPase- and Wnt-mediated effects imply constitutive, i.e., (pro)renin-independent functions of the (P)RR. Regarding ligand-dependent (P)RR signalling, the role of prorenin glycosylation is currently unknown. Therefore, the aim of this study was to analyse the contribution of constitutive (P)RR activity to its cellular effects and the relevance of prorenin glycosylation on its ligand activity. We were able to demonstrate that high glucose induces (P)RR signal transduction whereas deglycosylation of prorenin abolishes its intrinsic activity in neuronal and epithelial cells. By using siRNA against (P)RR or PLZF as well as the PLZF translocation blocker genistein and the specific V-ATPase inhibitor bafilomycin, we were able to dissect three distinct sub-pathways downstream of the (P)RR. The V-ATPase function is ligand-independently associated with strong pro-proliferative effects whereas prorenin causes moderate proliferation in vitro. In contrast, PLZF per se [i.e., in the absence of (pro)renin] does not interfere with cell number.
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kirsch
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Schrezenmeier
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Klare
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zaade
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Seidel
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schmitz
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bernhard
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Dilyara
authors.initials: D
authors.lastname: Lauer
authors.affiliation: Evotec AG, Hamburg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Slack
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Goldin-Lang
authors.affiliation: School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Zollmann
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Funke-Kaiser
mesh_terms: D000818:Animals; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006031:Glycosylation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D000093342:Prorenin Receptor
chemical_list: D019833:Genistein; D005947:Glucose; D051741:Kruppel-Like Transcription Factors; D018942:Macrolides; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D025262:Vacuolar Proton-Translocating ATPases; C458319:ATP6AP2 protein, human; D000093342:Prorenin Receptor; C057620:bafilomycin A; C092037:ZBTB16 protein, human