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

Nature Medicine volume 17, pages 1242–1250 (2011)Cite this article

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An Erratum to this article was published on 07 November 2011

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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.

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Figure 1: Induction of renal HB-EGF synthesis leads to glomerular activation of EGFR during RPGN.
Figure 2: HB-EGF induces a migratory phenotype in podocytes in vitro.
Figure 3: Deletion of Hbegf gene prevents fatal renal destruction.
Figure 4: Selective deletion of Egfr from podocytes protects from RPGN.
Figure 5: Delayed EGFR tyrosine kinase inhibition stops development of crescentic RPGN.
Figure 6: HB-EGF expression is induced in human crescentic glomerulonephritis.

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  • 07 November 2011

     In the version of this article initially published, the affiliations of the author Nathalie Sabaa were misidentified as affiliations 3 and 4. Her correct affiliations are 6 and 7. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

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.

Author information

Author notes

  1. Guillaume Bollée and Martin Flamant: These authors contributed equally to this work.

Authors and Affiliations

  1. Unité Mixte de Recherche (UMR) 970, Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

    Guillaume Bollée, Cécile Fligny, Marine Milon & Pierre-Louis Tharaux

  2. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Guillaume Bollée, Cécile Fligny, Marine Milon & Pierre-Louis Tharaux

  3. Université Paris Diderot, Sorbonne Paris Cité, Paris, France

    Martin Flamant

  4. Service de Physiologie–Explorations Fonctionnelles, Hôpital Bichat, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France

    Martin Flamant

  5. Institut für Anatomie und Zellbiologie, Universitätsmedizin Greifswald, Greifswald, Germany

    Sandra Schordan, Elisabeth Rumpel, Eric Schordan, Karlhans Endlich & Nicole Endlich

  6. INSERM UMR702, Hôpital Tenon, Paris, France

    Nathalie Sabaa, Sophie Vandermeersch, Jean-Claude Dussaule & Laurent Mesnard

  7. Université Pierre et Marie Curie, Sorbonne Universités, Paris, France

    Nathalie Sabaa, Sophie Vandermeersch, Jean-Claude Dussaule, Laurent Mesnard & Patrice Callard

  8. Centre for Interdisciplinary Research in Biology, Centre National de la Recherche Scientifique UMR 7241, INSERM U1050, Paris, France

    Ariane Galaup & Stéphane Germain

  9. Chaire de Médecine Expérimentale, Collège de France, Paris, France

    Ariane Galaup & Stéphane Germain

  10. Service d'Anatomie et de Cytologie Pathologiques, AP-HP, Hôpital Tenon, Paris, France

    Anita Rodenas & Patrice Callard

  11. INSERM UMR 1004, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France

    Ibrahim Casal & Claude Boucheix

  12. Université Paris-Sud, Villejuif, France

    Ibrahim Casal & Claude Boucheix

  13. The Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Susan W Sunnarborg

  14. Renal Section, Boston University Medical Center, Boston, Massachusetts, USA

    David J Salant

  15. Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA

    Jeffrey B Kopp

  16. Department of Genetics, North Carolina State University, Raleigh, North Carolina, USA

    David W Threadgill

  17. St. Michael's Hospital, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

    Susan E Quaggin

  18. Service de Physiologie-Exploration Fonctionnelles, AP-HP, Hôpital Saint-Antoine, Paris, France

    Jean-Claude Dussaule

  19. Service de Néphrologie et Dialyse, Centre Hospitalier Intercommunal André Grégoire, Montreuil, France

    Xavier Belenfant

  20. Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Paris, France

    Pierre-Louis Tharaux

Authors
  1. Guillaume Bollée
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  2. Martin Flamant
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Contributions

M.F., G.B. and P.-L.T. conceived the project and experiments. P.-L.T. and N.E. supervised the project. S.S., C.F., M.M., S.V. and E.S. developed methods to culture and analyze primary podocytes and conceived experiments for gene expression analysis. E.R. and M.M. carried out electron microscopy (EM) studies. S.W.S., S.E.Q., J.B.K., D.W.T., I.C. and C.B. helped generate mice with targeted deficiency of HBEGF, TGF-α, epiregulin and Egfr. A.G. and S.G. carried out in situ hybridization studies. D.J.S. and L.M. provided nephrotoxic serum and discussed data with P.-L.T. K.E., C.B. and J.-C.D. also discussed experiments with P.-L.T. and N.E. P.-L.T., G.B., M.M., C.F. and N.S. carried out all in vivo studies. M.F., A.R. and P.C. analyzed human kidney biopsies collected by X.B. G.B. and M.F. contributed equally to the study.

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Correspondence to Pierre-Louis Tharaux.

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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). https://doi.org/10.1038/nm.2491

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