title: Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis.
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.
authors.affiliation: Unité Mixte de Recherche (UMR) 970, Paris Cardiovascular Research Centre, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bollée
authors.forename: Martin
authors.initials: M
authors.lastname: Flamant
authors.forename: Sandra
authors.initials: S
authors.lastname: Schordan
authors.forename: Cécile
authors.initials: C
authors.lastname: Fligny
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rumpel
authors.forename: Marine
authors.initials: M
authors.lastname: Milon
authors.forename: Eric
authors.initials: E
authors.lastname: Schordan
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sabaa
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.forename: Ariane
authors.initials: A
authors.lastname: Galaup
authors.forename: Anita
authors.initials: A
authors.lastname: Rodenas
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Casal
authors.forename: Susan W
authors.initials: SW
authors.lastname: Sunnarborg
authors.forename: David J
authors.initials: DJ
authors.lastname: Salant
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: David W
authors.initials: DW
authors.lastname: Threadgill
authors.forename: Susan E
authors.initials: SE
authors.lastname: Quaggin
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.forename: Karlhans
authors.initials: K
authors.lastname: Endlich
authors.forename: Claude
authors.initials: C
authors.lastname: Boucheix
authors.forename: Xavier
authors.initials: X
authors.lastname: Belenfant
authors.forename: Patrice
authors.initials: P
authors.lastname: Callard
authors.forename: Nicole
authors.initials: N
authors.lastname: Endlich
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000166:cytology / Q000293:injuries* / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism; D011799:Quinazolines; D060888:Real-Time Polymerase Chain Reaction; D051437:Renal Insufficiency / Q000209:etiology*; D018709:Statistics, Nonparametric; D020032:Tyrphostins
chemical_list: C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors