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

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 SW, Salant DJ, Kopp JB, Threadgill DW, Quaggin SE, Dussaule JC, Germain S, Mesnard L, Endlich K, Boucheix C, Belenfant X, Callard P, Endlich N, Tharaux PL - Nat. Med. (2011)

Bottom Line: Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro.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.

View Article: PubMed Central - PubMed

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

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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Delayed EGFR tyrosine kinase inhibition stops the development of crescentic RPGN(a) Quantification by western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), NTS-injected mice treated with vehicle alone, and NTS-injected mice treated with erlotinib either started twelve hours before administration of NTS (days 0–14) or in a curative protocol, started four days later (d4–14). Mice were euthanised after 14 days of RPGN. (b) Blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in CT in the different groups of mice as in (a). Data are means ± sem, (n=9 mice per group). ** P<0.01 versus controls at baseline (CT), *** P<0.001 versus CT, ## P<0.01 versus vehicle, ## P<0.001 versus vehicle.(d) Ultrastructural analysis of podocytes by transmission electron microscopy in erlotinib-treated and vehicle-treated mice, five days after injection of NTS. Scale bar 2 μm.(e) Masson trichrome staining of renal cortex from a mouse treated with erlotinib (day 4–14) (left panel) and a vehicle-treated mouse (right panel) on day 14. Ne: necrotic glomerular lesions, Cr: cellular crescents, Tc: tubular proteinaceous casts, Infilt: diffuse CD3-positive cell infiltrates (Infilt) seen in vehicle-treated mice. Scale bar 100 μm.
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Figure 5: Delayed EGFR tyrosine kinase inhibition stops the development of crescentic RPGN(a) Quantification by western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), NTS-injected mice treated with vehicle alone, and NTS-injected mice treated with erlotinib either started twelve hours before administration of NTS (days 0–14) or in a curative protocol, started four days later (d4–14). Mice were euthanised after 14 days of RPGN. (b) Blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in CT in the different groups of mice as in (a). Data are means ± sem, (n=9 mice per group). ** P<0.01 versus controls at baseline (CT), *** P<0.001 versus CT, ## P<0.01 versus vehicle, ## P<0.001 versus vehicle.(d) Ultrastructural analysis of podocytes by transmission electron microscopy in erlotinib-treated and vehicle-treated mice, five days after injection of NTS. Scale bar 2 μm.(e) Masson trichrome staining of renal cortex from a mouse treated with erlotinib (day 4–14) (left panel) and a vehicle-treated mouse (right panel) on day 14. Ne: necrotic glomerular lesions, Cr: cellular crescents, Tc: tubular proteinaceous casts, Infilt: diffuse CD3-positive cell infiltrates (Infilt) seen in vehicle-treated mice. Scale bar 100 μm.

Mentions: To determine whether inhibition of the EGFR pathway could represent a therapeutic option for RPGN, we administered a clinically available EGFR inhibitor, erlotinib, on day 4 after infusion of anti-GBM serum. This time point was chosen because it is when albuminuria and acute renal failure peak, and thus a time that is relevant to clinical applications. This regimen was compared to the effect of vehicle alone and to the administration of erlotinib 12 hours before the first infusion of anti-GBM serum. The dose of erlotinib used significantly inhibited EGFR phosphorylation after 14 days of experimental RPGN (Fig. 5a). Again, “preventive” EGFR tyrosine kinase inhibition reduced the proportion of crescentic glomeruli (erlotinib-treated vs. vehicle only-treated group; P<0.01) (Fig. 5b), and the rise in BUN (P<0.01) (Fig. 5c). Erlotinib treatment also attenuated ultrastructural alterations of podocytes and full loss of interdigitating foot process pattern. (Fig. 5d). Overall, early and delayed erlotinib administration had similar marked therapeutic effects on renal damage, inflammation and renal failure in our experimental model (Fig. 5b–d).


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

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 SW, Salant DJ, Kopp JB, Threadgill DW, Quaggin SE, Dussaule JC, Germain S, Mesnard L, Endlich K, Boucheix C, Belenfant X, Callard P, Endlich N, Tharaux PL - Nat. Med. (2011)

Delayed EGFR tyrosine kinase inhibition stops the development of crescentic RPGN(a) Quantification by western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), NTS-injected mice treated with vehicle alone, and NTS-injected mice treated with erlotinib either started twelve hours before administration of NTS (days 0–14) or in a curative protocol, started four days later (d4–14). Mice were euthanised after 14 days of RPGN. (b) Blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in CT in the different groups of mice as in (a). Data are means ± sem, (n=9 mice per group). ** P<0.01 versus controls at baseline (CT), *** P<0.001 versus CT, ## P<0.01 versus vehicle, ## P<0.001 versus vehicle.(d) Ultrastructural analysis of podocytes by transmission electron microscopy in erlotinib-treated and vehicle-treated mice, five days after injection of NTS. Scale bar 2 μm.(e) Masson trichrome staining of renal cortex from a mouse treated with erlotinib (day 4–14) (left panel) and a vehicle-treated mouse (right panel) on day 14. Ne: necrotic glomerular lesions, Cr: cellular crescents, Tc: tubular proteinaceous casts, Infilt: diffuse CD3-positive cell infiltrates (Infilt) seen in vehicle-treated mice. Scale bar 100 μm.
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Figure 5: Delayed EGFR tyrosine kinase inhibition stops the development of crescentic RPGN(a) Quantification by western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), NTS-injected mice treated with vehicle alone, and NTS-injected mice treated with erlotinib either started twelve hours before administration of NTS (days 0–14) or in a curative protocol, started four days later (d4–14). Mice were euthanised after 14 days of RPGN. (b) Blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in CT in the different groups of mice as in (a). Data are means ± sem, (n=9 mice per group). ** P<0.01 versus controls at baseline (CT), *** P<0.001 versus CT, ## P<0.01 versus vehicle, ## P<0.001 versus vehicle.(d) Ultrastructural analysis of podocytes by transmission electron microscopy in erlotinib-treated and vehicle-treated mice, five days after injection of NTS. Scale bar 2 μm.(e) Masson trichrome staining of renal cortex from a mouse treated with erlotinib (day 4–14) (left panel) and a vehicle-treated mouse (right panel) on day 14. Ne: necrotic glomerular lesions, Cr: cellular crescents, Tc: tubular proteinaceous casts, Infilt: diffuse CD3-positive cell infiltrates (Infilt) seen in vehicle-treated mice. Scale bar 100 μm.
Mentions: To determine whether inhibition of the EGFR pathway could represent a therapeutic option for RPGN, we administered a clinically available EGFR inhibitor, erlotinib, on day 4 after infusion of anti-GBM serum. This time point was chosen because it is when albuminuria and acute renal failure peak, and thus a time that is relevant to clinical applications. This regimen was compared to the effect of vehicle alone and to the administration of erlotinib 12 hours before the first infusion of anti-GBM serum. The dose of erlotinib used significantly inhibited EGFR phosphorylation after 14 days of experimental RPGN (Fig. 5a). Again, “preventive” EGFR tyrosine kinase inhibition reduced the proportion of crescentic glomeruli (erlotinib-treated vs. vehicle only-treated group; P<0.01) (Fig. 5b), and the rise in BUN (P<0.01) (Fig. 5c). Erlotinib treatment also attenuated ultrastructural alterations of podocytes and full loss of interdigitating foot process pattern. (Fig. 5d). Overall, early and delayed erlotinib administration had similar marked therapeutic effects on renal damage, inflammation and renal failure in our experimental model (Fig. 5b–d).

Bottom Line: Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro.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.

View Article: PubMed Central - PubMed

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

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.

Show MeSH
Related in: MedlinePlus