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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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Deletion of Hbegf gene prevents fatal renal destruction(a) Survival curve for challenged Hbegf (+/+) and Hbegf (−/−) mice. In all cases, death was associated with severe renal damage with macroscopic hematuria (blood leakage into the urine) and animals died from renal failure (with 100% crescentic and necrotizing lesions at autopsy). (b) Masson Trichrome staining of kidneys and proportion of crescentic glomeruli in control mice and in NTS-injected Hbegf (+/+) and Hbegf (−/−) mice (day 8 post NTS) (Cr: crescents, G: glomeruli, Tc: tubules with proteinaceous casts) Scale bar, 50μm. (c) Ascites score as an index of albumin plasma loss and water and sodium retention, (d) albuminuria and (e) blood urea nitrogen concentrations in NTS-challenged Hbegf (+/+) and Hbegf (−/−) animals on day 8 post NTS, and in unchallenged controls (CT). Values reported are means ± sem. (n=9–12 per group). * P<0.05 versus controls at baseline, ** P<0.01 versus baseline, *** P<0.001 versus baseline. # P<0.05 versus NTS-treated (+/+), ## P<0.01 versus NTS-treated (+/+).
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Figure 3: Deletion of Hbegf gene prevents fatal renal destruction(a) Survival curve for challenged Hbegf (+/+) and Hbegf (−/−) mice. In all cases, death was associated with severe renal damage with macroscopic hematuria (blood leakage into the urine) and animals died from renal failure (with 100% crescentic and necrotizing lesions at autopsy). (b) Masson Trichrome staining of kidneys and proportion of crescentic glomeruli in control mice and in NTS-injected Hbegf (+/+) and Hbegf (−/−) mice (day 8 post NTS) (Cr: crescents, G: glomeruli, Tc: tubules with proteinaceous casts) Scale bar, 50μm. (c) Ascites score as an index of albumin plasma loss and water and sodium retention, (d) albuminuria and (e) blood urea nitrogen concentrations in NTS-challenged Hbegf (+/+) and Hbegf (−/−) animals on day 8 post NTS, and in unchallenged controls (CT). Values reported are means ± sem. (n=9–12 per group). * P<0.05 versus controls at baseline, ** P<0.01 versus baseline, *** P<0.001 versus baseline. # P<0.05 versus NTS-treated (+/+), ## P<0.01 versus NTS-treated (+/+).

Mentions: Twelve Hbegf (−/−) and 14 Hbegf (+/+) male littermates had similar renal histology and functional parameters (microalbuminuria, serum creatinine and blood urea nitrogen (BUN)) at baseline (not shown). Therefore, we used pre-immunized but unchallenged Hbegf (+/+) mice as baseline controls (CT), unless otherwise specified. Histological examination of NTS injected Hbegf (+/+) mice revealed severe glomerulonephritis and reduced survival by day 8 (Fig. 3a). while Hbegf (−/−) littermates were significantly spared from renal damage (Fig. 3b). Nephrotic syndrome is caused by hypoproteinemia due to massive urinary loss of large proteins, particularly albumin, ensuing hypoalbuminemia and is reflected by ascites. HB-EGF deficiency significantly prevented both incidence and severity of ascites (Fig. 3c) as well as renal dysfunction as reflected by albuminuria (Fig. 3d) and also by BUN concentrations, which kept within normal range in Hbegf (−/−) (Fig. 3e). Consistent with renal protection associated with lack of HB-EGF, all Hbegf (−/−) animals survived whereas 30% of Hbegf (+/+) littermates died within 8 days (P<0.01, Fig. 3a) with nearly 100% crescentic glomeruli and terminal renal failure (not shown). Similar protective effects of HB-EGF deficiency were observed in an independent experiment where animals were followed for 21 days (not shown).


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)

Deletion of Hbegf gene prevents fatal renal destruction(a) Survival curve for challenged Hbegf (+/+) and Hbegf (−/−) mice. In all cases, death was associated with severe renal damage with macroscopic hematuria (blood leakage into the urine) and animals died from renal failure (with 100% crescentic and necrotizing lesions at autopsy). (b) Masson Trichrome staining of kidneys and proportion of crescentic glomeruli in control mice and in NTS-injected Hbegf (+/+) and Hbegf (−/−) mice (day 8 post NTS) (Cr: crescents, G: glomeruli, Tc: tubules with proteinaceous casts) Scale bar, 50μm. (c) Ascites score as an index of albumin plasma loss and water and sodium retention, (d) albuminuria and (e) blood urea nitrogen concentrations in NTS-challenged Hbegf (+/+) and Hbegf (−/−) animals on day 8 post NTS, and in unchallenged controls (CT). Values reported are means ± sem. (n=9–12 per group). * P<0.05 versus controls at baseline, ** P<0.01 versus baseline, *** P<0.001 versus baseline. # P<0.05 versus NTS-treated (+/+), ## P<0.01 versus NTS-treated (+/+).
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Related In: Results  -  Collection

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Figure 3: Deletion of Hbegf gene prevents fatal renal destruction(a) Survival curve for challenged Hbegf (+/+) and Hbegf (−/−) mice. In all cases, death was associated with severe renal damage with macroscopic hematuria (blood leakage into the urine) and animals died from renal failure (with 100% crescentic and necrotizing lesions at autopsy). (b) Masson Trichrome staining of kidneys and proportion of crescentic glomeruli in control mice and in NTS-injected Hbegf (+/+) and Hbegf (−/−) mice (day 8 post NTS) (Cr: crescents, G: glomeruli, Tc: tubules with proteinaceous casts) Scale bar, 50μm. (c) Ascites score as an index of albumin plasma loss and water and sodium retention, (d) albuminuria and (e) blood urea nitrogen concentrations in NTS-challenged Hbegf (+/+) and Hbegf (−/−) animals on day 8 post NTS, and in unchallenged controls (CT). Values reported are means ± sem. (n=9–12 per group). * P<0.05 versus controls at baseline, ** P<0.01 versus baseline, *** P<0.001 versus baseline. # P<0.05 versus NTS-treated (+/+), ## P<0.01 versus NTS-treated (+/+).
Mentions: Twelve Hbegf (−/−) and 14 Hbegf (+/+) male littermates had similar renal histology and functional parameters (microalbuminuria, serum creatinine and blood urea nitrogen (BUN)) at baseline (not shown). Therefore, we used pre-immunized but unchallenged Hbegf (+/+) mice as baseline controls (CT), unless otherwise specified. Histological examination of NTS injected Hbegf (+/+) mice revealed severe glomerulonephritis and reduced survival by day 8 (Fig. 3a). while Hbegf (−/−) littermates were significantly spared from renal damage (Fig. 3b). Nephrotic syndrome is caused by hypoproteinemia due to massive urinary loss of large proteins, particularly albumin, ensuing hypoalbuminemia and is reflected by ascites. HB-EGF deficiency significantly prevented both incidence and severity of ascites (Fig. 3c) as well as renal dysfunction as reflected by albuminuria (Fig. 3d) and also by BUN concentrations, which kept within normal range in Hbegf (−/−) (Fig. 3e). Consistent with renal protection associated with lack of HB-EGF, all Hbegf (−/−) animals survived whereas 30% of Hbegf (+/+) littermates died within 8 days (P<0.01, Fig. 3a) with nearly 100% crescentic glomeruli and terminal renal failure (not shown). Similar protective effects of HB-EGF deficiency were observed in an independent experiment where animals were followed for 21 days (not shown).

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