title: Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury.
abstract: Glomerular crescents are most common in rapidly progressive glomerulonephritis but also occur in non-inflammatory chronic glomerulopathies; thus, factors other than inflammation should trigger crescent formation, eg vascular damage and plasma leakage. Here we report that Alport nephropathy in Col4A3-deficient Sv129 mice is complicated by diffuse and global crescent formation in which proliferating parietal epithelial cells are the predominant cell type. Laminin staining and transmission and acellular scanning electron microscopy of acellular glomeruli documented disruptions and progressive disintegration of the glomerular basement membrane in Col4A3-deficient mice. FITC-dextran perfusion further revealed vascular leakage from glomerular capillaries into Bowman's space, further documented by fibrin deposits in the segmental crescents. Its pathogenic role was validated by showing that the fibrinolytic activity of recombinant urokinase partially prevented crescent formation. In addition, in vitro studies confirmed an additional mitogenic potential of serum on murine and human parietal epithelial cells. Furthermore, loss of parietal cell polarity and unpolarized secretion of extracellular matrix components were evident within fibrocellular crescents. Among 665 human Alport nephropathy biopsies, crescent formation was noted in 0.4%. We conclude that glomerular vascular injury and GBM breaks cause plasma leakage which triggers a wound healing programme involving the proliferation of parietal cells and their loss of polarity. This process can trigger cellular and fibrocellular crescent formation even in the absence of cellular inflammation and rupture of the Bowman's capsule.
authors.affiliation: Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Germany.
authors.forename: Mi
authors.initials: M
authors.lastname: Ryu
authors.forename: Adriana
authors.initials: A
authors.lastname: Migliorini
authors.forename: Nicolai
authors.initials: N
authors.lastname: Miosge
authors.forename: Oliver
authors.initials: O
authors.lastname: Gross
authors.forename: Stuart
authors.initials: S
authors.lastname: Shankland
authors.forename: Paul T
authors.initials: PT
authors.lastname: Brinkkoetter
authors.forename: Henning
authors.initials: H
authors.lastname: Hagmann
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.forename: Helen
authors.initials: H
authors.lastname: Liapis
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D001798:Blood Proteins / Q000494:pharmacology; D002461:Cell Line, Transformed; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D024141:Collagen Type IV / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D050533:Glomerular Basement Membrane / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D061251:Primary Cell Culture; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology; D014945:Wound Healing / Q000502:physiology
chemical_list: D001324:Autoantigens; D001798:Blood Proteins; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain; D014568:Urokinase-Type Plasminogen Activator