Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis

Guillaume Bollée, Martin Flamant, Sandra Schordan, Cécile Fligny, Elisabeth Rumpel, Marine Milon, Eric Schordan, Nathalie Sabaa, Sophie Vandermeersch, Ariane Galaup, Anita Rodenas, Ibrahim Casal, Susan W. Sunnarborg, David J. Salant, Jeffrey B. Kopp, David W. Threadgill, Susan E. Quaggin, Jean Claude Dussaule, Stéphane Germain, Laurent MesnardKarlhans Endlich, Claude Boucheix, Xavier Belenfant, Patrice Callard, Nicole Endlich, Pierre Louis Tharaux*

*Corresponding author for this work

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

Rapidly progressive glomerulonephritis (RPGN) is a life-threatening clinical syndrome and a morphological manifestation of severe glomerular injury that is marked by a proliferative histological pattern ('crescents') with accumulation of T cells and macrophages and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the epidermal growth factor receptor (EGFR, also known as ErbB1) in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Likewise, pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 d after the induction of experimental RPGN. This suggests that targeting the HB-EGF-EGFR pathway could also be beneficial in treatment of human RPGN.

Original languageEnglish (US)
Pages (from-to)1242-1250
Number of pages9
JournalNature Medicine
Volume17
Issue number10
DOIs
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Bollée, G., Flamant, M., Schordan, S., Fligny, C., Rumpel, E., Milon, M., Schordan, E., Sabaa, N., Vandermeersch, S., Galaup, A., Rodenas, A., Casal, I., Sunnarborg, S. W., Salant, D. J., Kopp, J. B., Threadgill, D. W., Quaggin, S. E., Dussaule, J. C., Germain, S., ... Tharaux, P. L. (2011). Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nature Medicine, 17(10), 1242-1250. https://doi.org/10.1038/nm.2491