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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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HB-EGF expression is induced in human crescentic glomerulonephritisRepresentative images of immunostaining for HB-EGF using monoclonal sc-74526 antibody in sections of kidney biopsies from 8 random subjects diagnosed with non crescentic glomerulopathies (upper panels), including diabetic nephropathy, amyloidosis, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). Similarly, lower panels show immunostaining for HB-EGF in renal biopsies from 8 random subjects RPGN of various etiologies, including lupus nephritis, microscopic polyangiitis (MP), endocarditis (End), Goodpasture disease (Gp), and Wegener disease (Wg). Scale bar 50 μm.
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Figure 6: HB-EGF expression is induced in human crescentic glomerulonephritisRepresentative images of immunostaining for HB-EGF using monoclonal sc-74526 antibody in sections of kidney biopsies from 8 random subjects diagnosed with non crescentic glomerulopathies (upper panels), including diabetic nephropathy, amyloidosis, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). Similarly, lower panels show immunostaining for HB-EGF in renal biopsies from 8 random subjects RPGN of various etiologies, including lupus nephritis, microscopic polyangiitis (MP), endocarditis (End), Goodpasture disease (Gp), and Wegener disease (Wg). Scale bar 50 μm.

Mentions: To evaluate the relevance of these findings to human disease, we used immunostaining with three unrelated antibodies to human HB-EGF to address upregulation of HB-EGF in glomeruli from subjects with crescentic RPGN (Supplementary Fig. 8a). All three antibodies displayed similar patterns of HB-EGF labelling both in normal human kidney and in renal biopsies from subjects with RPGN (Supplementary Fig. 8a). In normal human kidneys, HB-EGF labelling was weak and restricted to tubules and vascular smooth muscle cells (Supplementary Fig. 8a). Little or no epithelial expression of HB-EGF was found in glomeruli from subjects diagnosed with noncrescentic glomerulopathies (Fig. 6). HB-EGF labelling in glomeruli from subjects with crescentic RPGN was substantially stronger overall, particularly in podocytes, in parietal epithelial cells (Fig. 6 and Supplementary Fig. 8b), and in tubules. Moreover, HB-EGF staining was more intense and diffuse in glomeruli with crescents than in less affected glomeruli within the same tissue samples (Supplementary Fig. 8a). Weaker but consistent HB-EGF expression was also observed in inflammatory infiltrates (Supplementary Fig. 8b). A similar pattern or HBEGF expression was observed in all kidney samples with RPGN whatever the immune cause (Fig. 6 and Supplementary Fig. 8b). These studies show that HB-EGF is specifically increased, sometimes in a sustained fashion, in conditions associated with crescent formation and immune destruction of the glomeruli.


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)

HB-EGF expression is induced in human crescentic glomerulonephritisRepresentative images of immunostaining for HB-EGF using monoclonal sc-74526 antibody in sections of kidney biopsies from 8 random subjects diagnosed with non crescentic glomerulopathies (upper panels), including diabetic nephropathy, amyloidosis, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). Similarly, lower panels show immunostaining for HB-EGF in renal biopsies from 8 random subjects RPGN of various etiologies, including lupus nephritis, microscopic polyangiitis (MP), endocarditis (End), Goodpasture disease (Gp), and Wegener disease (Wg). Scale bar 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198052&req=5

Figure 6: HB-EGF expression is induced in human crescentic glomerulonephritisRepresentative images of immunostaining for HB-EGF using monoclonal sc-74526 antibody in sections of kidney biopsies from 8 random subjects diagnosed with non crescentic glomerulopathies (upper panels), including diabetic nephropathy, amyloidosis, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). Similarly, lower panels show immunostaining for HB-EGF in renal biopsies from 8 random subjects RPGN of various etiologies, including lupus nephritis, microscopic polyangiitis (MP), endocarditis (End), Goodpasture disease (Gp), and Wegener disease (Wg). Scale bar 50 μm.
Mentions: To evaluate the relevance of these findings to human disease, we used immunostaining with three unrelated antibodies to human HB-EGF to address upregulation of HB-EGF in glomeruli from subjects with crescentic RPGN (Supplementary Fig. 8a). All three antibodies displayed similar patterns of HB-EGF labelling both in normal human kidney and in renal biopsies from subjects with RPGN (Supplementary Fig. 8a). In normal human kidneys, HB-EGF labelling was weak and restricted to tubules and vascular smooth muscle cells (Supplementary Fig. 8a). Little or no epithelial expression of HB-EGF was found in glomeruli from subjects diagnosed with noncrescentic glomerulopathies (Fig. 6). HB-EGF labelling in glomeruli from subjects with crescentic RPGN was substantially stronger overall, particularly in podocytes, in parietal epithelial cells (Fig. 6 and Supplementary Fig. 8b), and in tubules. Moreover, HB-EGF staining was more intense and diffuse in glomeruli with crescents than in less affected glomeruli within the same tissue samples (Supplementary Fig. 8a). Weaker but consistent HB-EGF expression was also observed in inflammatory infiltrates (Supplementary Fig. 8b). A similar pattern or HBEGF expression was observed in all kidney samples with RPGN whatever the immune cause (Fig. 6 and Supplementary Fig. 8b). These studies show that HB-EGF is specifically increased, sometimes in a sustained fashion, in conditions associated with crescent formation and immune destruction of the glomeruli.

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