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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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Induction of renal HB-EGF synthesis leads to glomerular activation of EGFR during RPGN(a) Representative image of in situ hybridization study in NTS-injected wild-type (Hbegf (+/+)) animals, showing proHB-EGF expression in glomeruli (G), especially in parietal glomerular epithelial cells (Pec), in podocytes (day 4) and in crescents (Cr) (day 8). White arrow indicates abundant proHB-EGF mRNA expression in areas where tuft-capsular podocyte bridges were present. Scale bar (orange), 50 μm. (b) Quantification by real-time RT-PCR of proHB-EGF mRNA in freshly isolated podocytes on day 6 after nephrotoxic serum injection (NTS) and in podocytes from non-injected control mice (CT) (n=3 per group). * P<0.05 versus controls. (c) Western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), wild-type (Hbegf (+/+)) mice infused with NTS ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from Hbegf (+/+) animals that were given intraperitoneal injections of the EGFR tyrosine kinase inhibitor AG1478 ((+/+)NTS+AG1478). Values reported are means ± sem. (n=6–8 per group). (d) Immunofluorescence staining for phosphoEGFR in renal cortex from controls (CT), NTS-injected Hbegf (+/+) mice ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from NTS-injected Hbegf (+/+) animals treated by AG1478 ((+/+)NTS+AG1478), on day 8 after NTS administration. * P<0.05 versus controls at baseline, ** P<0.01 versus controls at baseline. ## P<0.01 versus mice treated with vehicle only. Pec: parietal glomerular epithelial cells; G: glomerulus; Cr: crescent.
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Figure 1: Induction of renal HB-EGF synthesis leads to glomerular activation of EGFR during RPGN(a) Representative image of in situ hybridization study in NTS-injected wild-type (Hbegf (+/+)) animals, showing proHB-EGF expression in glomeruli (G), especially in parietal glomerular epithelial cells (Pec), in podocytes (day 4) and in crescents (Cr) (day 8). White arrow indicates abundant proHB-EGF mRNA expression in areas where tuft-capsular podocyte bridges were present. Scale bar (orange), 50 μm. (b) Quantification by real-time RT-PCR of proHB-EGF mRNA in freshly isolated podocytes on day 6 after nephrotoxic serum injection (NTS) and in podocytes from non-injected control mice (CT) (n=3 per group). * P<0.05 versus controls. (c) Western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), wild-type (Hbegf (+/+)) mice infused with NTS ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from Hbegf (+/+) animals that were given intraperitoneal injections of the EGFR tyrosine kinase inhibitor AG1478 ((+/+)NTS+AG1478). Values reported are means ± sem. (n=6–8 per group). (d) Immunofluorescence staining for phosphoEGFR in renal cortex from controls (CT), NTS-injected Hbegf (+/+) mice ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from NTS-injected Hbegf (+/+) animals treated by AG1478 ((+/+)NTS+AG1478), on day 8 after NTS administration. * P<0.05 versus controls at baseline, ** P<0.01 versus controls at baseline. ## P<0.01 versus mice treated with vehicle only. Pec: parietal glomerular epithelial cells; G: glomerulus; Cr: crescent.

Mentions: We tested for proHB-EGF mRNA by real-time RT-PCR in kidneys harvested 8 days after injection of nephrotoxic serum (NTS) into mice: proHB-EGF mRNA was three times more abundant in treated than control animals (proHB-EGF cDNA / 18S cDNA ratio 10.8 ± 1.7 vs. 3.5 ± 1.4, respectively, n=6, P<0.05) (not shown). Four days after NTS injection and before the first appearance of crescents, proHB-EGF mRNA was detected in parietal epithelial glomerular cells and podocytes. On day 8, crescents were observed and in situ hybridisation showed diffuse proHB-EGF mRNA labelling (Fig. 1a). In freshly isolated podocytes proHB-EGF mRNA was increased 3.6± 0.4-fold 6 days after NTS injection as compared to untreated controls (n=3 per group, P<0.05) (Fig. 1b).


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)

Induction of renal HB-EGF synthesis leads to glomerular activation of EGFR during RPGN(a) Representative image of in situ hybridization study in NTS-injected wild-type (Hbegf (+/+)) animals, showing proHB-EGF expression in glomeruli (G), especially in parietal glomerular epithelial cells (Pec), in podocytes (day 4) and in crescents (Cr) (day 8). White arrow indicates abundant proHB-EGF mRNA expression in areas where tuft-capsular podocyte bridges were present. Scale bar (orange), 50 μm. (b) Quantification by real-time RT-PCR of proHB-EGF mRNA in freshly isolated podocytes on day 6 after nephrotoxic serum injection (NTS) and in podocytes from non-injected control mice (CT) (n=3 per group). * P<0.05 versus controls. (c) Western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), wild-type (Hbegf (+/+)) mice infused with NTS ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from Hbegf (+/+) animals that were given intraperitoneal injections of the EGFR tyrosine kinase inhibitor AG1478 ((+/+)NTS+AG1478). Values reported are means ± sem. (n=6–8 per group). (d) Immunofluorescence staining for phosphoEGFR in renal cortex from controls (CT), NTS-injected Hbegf (+/+) mice ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from NTS-injected Hbegf (+/+) animals treated by AG1478 ((+/+)NTS+AG1478), on day 8 after NTS administration. * P<0.05 versus controls at baseline, ** P<0.01 versus controls at baseline. ## P<0.01 versus mice treated with vehicle only. Pec: parietal glomerular epithelial cells; G: glomerulus; Cr: crescent.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198052&req=5

Figure 1: Induction of renal HB-EGF synthesis leads to glomerular activation of EGFR during RPGN(a) Representative image of in situ hybridization study in NTS-injected wild-type (Hbegf (+/+)) animals, showing proHB-EGF expression in glomeruli (G), especially in parietal glomerular epithelial cells (Pec), in podocytes (day 4) and in crescents (Cr) (day 8). White arrow indicates abundant proHB-EGF mRNA expression in areas where tuft-capsular podocyte bridges were present. Scale bar (orange), 50 μm. (b) Quantification by real-time RT-PCR of proHB-EGF mRNA in freshly isolated podocytes on day 6 after nephrotoxic serum injection (NTS) and in podocytes from non-injected control mice (CT) (n=3 per group). * P<0.05 versus controls. (c) Western blot analysis of phosphorylated EGFR and total EGFR in the renal cortex from non-challenged controls (CT), wild-type (Hbegf (+/+)) mice infused with NTS ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from Hbegf (+/+) animals that were given intraperitoneal injections of the EGFR tyrosine kinase inhibitor AG1478 ((+/+)NTS+AG1478). Values reported are means ± sem. (n=6–8 per group). (d) Immunofluorescence staining for phosphoEGFR in renal cortex from controls (CT), NTS-injected Hbegf (+/+) mice ((+/+)NTS), HB-EGF deficient mice infused with NTS ((−/−)NTS), and from NTS-injected Hbegf (+/+) animals treated by AG1478 ((+/+)NTS+AG1478), on day 8 after NTS administration. * P<0.05 versus controls at baseline, ** P<0.01 versus controls at baseline. ## P<0.01 versus mice treated with vehicle only. Pec: parietal glomerular epithelial cells; G: glomerulus; Cr: crescent.
Mentions: We tested for proHB-EGF mRNA by real-time RT-PCR in kidneys harvested 8 days after injection of nephrotoxic serum (NTS) into mice: proHB-EGF mRNA was three times more abundant in treated than control animals (proHB-EGF cDNA / 18S cDNA ratio 10.8 ± 1.7 vs. 3.5 ± 1.4, respectively, n=6, P<0.05) (not shown). Four days after NTS injection and before the first appearance of crescents, proHB-EGF mRNA was detected in parietal epithelial glomerular cells and podocytes. On day 8, crescents were observed and in situ hybridisation showed diffuse proHB-EGF mRNA labelling (Fig. 1a). In freshly isolated podocytes proHB-EGF mRNA was increased 3.6± 0.4-fold 6 days after NTS injection as compared to untreated controls (n=3 per group, P<0.05) (Fig. 1b).

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