title: Induction of B7-1 in podocytes is associated with nephrotic syndrome.
abstract: Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, New York, New York 10461, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Reiser
authors.forename: Gero
authors.initials: G
authors.lastname: von Gersdorff
authors.forename: Martin
authors.initials: M
authors.lastname: Loos
authors.forename: Jun
authors.initials: J
authors.lastname: Oh
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Asanuma
authors.forename: Laura
authors.initials: L
authors.lastname: Giardino
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.forename: Novella
authors.initials: N
authors.lastname: Calvaresi
authors.forename: Haruko
authors.initials: H
authors.lastname: Watanabe
authors.forename: Karin
authors.initials: K
authors.lastname: Schwarz
authors.forename: Christian
authors.initials: C
authors.lastname: Faul
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Anne
authors.initials: A
authors.lastname: Davidson
authors.forename: Hikaru
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Jordan A
authors.initials: JA
authors.lastname: Kreidberg
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D039422:Integrin alpha3 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008181:Lupus Nephritis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009404:Nephrotic Syndrome / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D000199:Actins; D018122:B7-1 Antigen; D039422:Integrin alpha3; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C113267:nephrin; D004247:DNA