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

2011; Nature Portfolio; Volume: 17; Issue: 10 Linguagem: Inglês

10.1038/nm.2491

1546-170X

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 Mesnard, Karlhans Endlich, Claude Boucheix, Xavier Belenfant, P Callard, Nicole Endlich, Pierre‐Louis Tharaux,

Autoimmune Bullous Skin Diseases

Rapidly progressive glomerulonephritis (RPGN) is a form of severe kidney injury that can lead to promptly lethal renal failure. Pierre-Louis Tharaux and colleagues report that HB-EGF is upregulated in RPGN, resulting in activation of EGFR in podocytes and their dysfunction. They further show that genetic loss of expression of HB-EGF or EGFR in a mouse model is protective, whereas pharmacological inhibition of EGFR, even after disease onset, is therapeutic. These results suggest a possible avenue of treatment for this potentially devastating condition. 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.