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.
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This work was supported by INSERM, grant ANR-08-EBIO-003 (P.-L.T.) from l'Agence Nationale de la Recherche of France, grant 01GN0805 (K.E.) from the German Federal Ministry of Education and Research (BMBF) and grants CA43793 (S.W.S.) and DK30932 (D.S.) from the US National Institutes of Health. We are grateful to la Fondation pour la Recherche Médicale and la Fondation Lefoulon-Delalande for supporting G.B. and C.F., respectively. We thank L.B. Holzman (Perelman School of Medicine, University of Pennsylvania) for the use of podocin-Cre mice crossed with Z/EGFP mice. We also thank X. Biolchini, C. Kitou, C. Martin, E. Huc and the ERI970 team for assistance in animal care and handling, H. Wegner, R. Maciejewski and T. Felix for technical assistance and J. Peters for help with fluorescence-activated cell sorting (FACS; supported by InnoProfile grant 03IP612 of the BMBF). We acknowledge administrative support from M.-C. Poeuf, V. Oberweiss, A. De Rueda, M. Autran and P. Coudol.
The authors declare no competing financial interests.
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Bollée, G., Flamant, M., Schordan, S. et al. Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med 17, 1242–1250 (2011) doi:10.1038/nm.2491
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