Induction of B7-1 in podocytes is associated with nephrotic syndrome
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Induction of B7-1 in podocytes is associated with nephrotic syndrome. / Reiser, Jochen; von Gersdorff, Gero; Loos, Martin; Oh, Jun; Asanuma, Katsuhiko; Giardino, Laura; Rastaldi, Maria Pia; Calvaresi, Novella; Watanabe, Haruko; Schwarz, Karin; Faul, Christian; Kretzler, Matthias; Davidson, Anne; Sugimoto, Hikaru; Kalluri, Raghu; Sharpe, Arlene H; Kreidberg, Jordan A; Mundel, Peter.
In: J CLIN INVEST, Vol. 113, No. 10, 05.2004, p. 1390-7.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Induction of B7-1 in podocytes is associated with nephrotic syndrome
AU - Reiser, Jochen
AU - von Gersdorff, Gero
AU - Loos, Martin
AU - Oh, Jun
AU - Asanuma, Katsuhiko
AU - Giardino, Laura
AU - Rastaldi, Maria Pia
AU - Calvaresi, Novella
AU - Watanabe, Haruko
AU - Schwarz, Karin
AU - Faul, Christian
AU - Kretzler, Matthias
AU - Davidson, Anne
AU - Sugimoto, Hikaru
AU - Kalluri, Raghu
AU - Sharpe, Arlene H
AU - Kreidberg, Jordan A
AU - Mundel, Peter
PY - 2004/5
Y1 - 2004/5
N2 - 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.
AB - 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.
KW - Actins/metabolism
KW - Animals
KW - B7-1 Antigen/biosynthesis
KW - Base Sequence
KW - DNA/genetics
KW - Humans
KW - In Vitro Techniques
KW - Integrin alpha3/genetics
KW - Kidney/immunology
KW - Lipopolysaccharides/toxicity
KW - Lupus Nephritis/etiology
KW - Membrane Glycoproteins/metabolism
KW - Membrane Proteins
KW - Mice
KW - Mice, Knockout
KW - Mice, SCID
KW - Nephrotic Syndrome/etiology
KW - Proteins/genetics
KW - Receptors, Cell Surface/metabolism
KW - Signal Transduction
KW - Toll-Like Receptor 4
KW - Toll-Like Receptors
U2 - 10.1172/JCI20402
DO - 10.1172/JCI20402
M3 - SCORING: Journal article
C2 - 15146236
VL - 113
SP - 1390
EP - 1397
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 10
ER -