title: Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren.
abstract: OBJECTIVE
  Inhibition of (pro)renin receptor activation was demonstrated to inhibit or even abolish the development of end-organ damage in animal models. The new renin inhibitor, aliskiren, markedly increases the plasma concentration of the (pro)renin receptor ligands prorenin and renin in patients. The effects of prorenin and of renin inhibitors on the signal transduction cascade of the (pro)renin receptor are currently unknown.
  
  
  RESULTS
  Our results indicate that renin and prorenin were equally potent in (pro)renin receptor activation by decreasing (pro)renin receptor mRNA, increasing phosphatidylinositol-3 kinase p85alpha mRNA and augmenting viable cell number, respectively. These effects of renin and prorenin are both abolished using small-interfering RNA against the (pro)renin receptor or its adaptor promyelocytic zinc finger protein. The renin inhibitor aliskiren did not inhibit the renin-induced or prorenin-induced activation of the (pro)renin receptor.
  
  
  CONCLUSIONS
  This is the first report demonstrating equal ligand activities of both, renin and prorenin, on the (pro)renin receptor - promyelocytic zinc finger protein-phosphatidylinositol-3 kinase-p85alpha pathway. The failure of aliskiren to inhibit the noncatalytic effects of renin and prorenin may be of clinical relevance considering the increase in plasma concentrations of (pro)renin under aliskiren treatment.
authors.affiliation: Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Hessische Strasse 3-4, Berlin, Germany.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Schefe
authors.forename: Christian
authors.initials: C
authors.lastname: Neumann
authors.forename: Matthias
authors.initials: M
authors.lastname: Goebel
authors.forename: Jan
authors.initials: J
authors.lastname: Danser
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kirsch
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Heiko
authors.initials: H
authors.lastname: Funke-Kaiser
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005650:Fumarates / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000378:metabolism* / Q000494:pharmacology; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D019869:Phosphatidylinositol 3-Kinases; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012083:Renin; D000093342:Prorenin Receptor; D000092502:Renin Inhibitors; C092037:ZBTB16 protein, human; C446481:aliskiren