Induction of B7-1 in podocytes is associated with nephrotic syndrome

Jochen Reiser, Gero Von Gersdorff, Martin Loos, Jun Oh, Katsuhiko Asanuma, Laura Giardino, Maria Pia Rastaldi, Novella Calvaresi, Haruko Watanabe, Karin Schwarz, Christian H Faul, Matthias Kretzler, Anne Davidson, Hikaru Sugimoto, Raghu Kalluri, Arlene H. Sharpe, Jordan A. Kreidberg, Peter Mundel

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1390-1397
Number of pages8
JournalJournal of Clinical Investigation
Volume113
Issue number10
DOIs
StatePublished - May 1 2004
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Reiser, J., Von Gersdorff, G., Loos, M., Oh, J., Asanuma, K., Giardino, L., Rastaldi, M. P., Calvaresi, N., Watanabe, H., Schwarz, K., Faul, C. H., Kretzler, M., Davidson, A., Sugimoto, H., Kalluri, R., Sharpe, A. H., Kreidberg, J. A., & Mundel, P. (2004). Induction of B7-1 in podocytes is associated with nephrotic syndrome. Journal of Clinical Investigation, 113(10), 1390-1397. https://doi.org/10.1172/JCI200420402