Limits...
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.

Show MeSH

Related in: MedlinePlus

Selective deletion of Egfr from podocytes protects from RPGN(a) Albuminuria (b) blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice, 8 days after NTS-induced RPGN (P<0.05 for all comparisons). (d) Survival curve of challenged Pod-Tet on-Cre EgfrloxP/loxP and littermate control mice in a severe model of RPGN. (* P<0.01). (e) Ultrastructural analysis of podocytes by transmission electron microscopy in NTS-treated Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice. More severe foot process effacement and irregular thickening of the GBM is visible in Pod-Tet on-Cre Egfrwt/wt animals. Scale bars: upper panels 2μm, lower panels 1μm.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198052&req=5

Figure 4: Selective deletion of Egfr from podocytes protects from RPGN(a) Albuminuria (b) blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice, 8 days after NTS-induced RPGN (P<0.05 for all comparisons). (d) Survival curve of challenged Pod-Tet on-Cre EgfrloxP/loxP and littermate control mice in a severe model of RPGN. (* P<0.01). (e) Ultrastructural analysis of podocytes by transmission electron microscopy in NTS-treated Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice. More severe foot process effacement and irregular thickening of the GBM is visible in Pod-Tet on-Cre Egfrwt/wt animals. Scale bars: upper panels 2μm, lower panels 1μm.

Mentions: To determine if EGFR expression in podocytes in vivo is necessary for crescent formation and renal failure, we selectively deleted Egfr from renal podocytes. We used a conditional expression model (Tet-On system) in which the target gene is deleted only in the presence of a tetracycline derivative to achieve temporal podocyte specific deletion of the Egfr gene in mice (Supplementary Fig. 5a,b). Mice of all genotypes were born at the expected Mendelian frequency and appeared healthy. Ten weeks after doxycyline administration, kidney histology was normal (Supplementary Fig. 5c), no apoptotic cells were observed in glomeruli (Supplementary Fig. 5d), and albuminuria was within physiological range (not shown). Ten Podocin-rtTA-Tet-O-Cre EgfrloxP/loxP males and 12 Podocin-rtTA-Tet-O-Cre Egfrwt/wt gender-matched littermates were subjected to severe, life-threatening RPGN with high dose NTS. Podocyte specific deletion of Egfr alleviated albumin urinary excretion (P<0.05) (Fig. 4a), the rise of BUN (P<0.05) (Fig. 4b), and crescent formation (P<0.05) (Fig. 4c) and completely protected mice from death (0% mortality vs. 66% mortality for control mice with unperturbed EGFR expression in podocytes; P<0.01; Fig. 4d). Improved kidney function and survival also correlated with less severe changes to podocyte ultrastructure in tetracycline induced Podocin-rtTA-Tet-O-Cre EgfrloxP/loxP mice relative to tetracycline induced Podocin-rtTA-Tet-O-Cre Egfrwt/wt littermate controls (Fig. 4e).


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)

Selective deletion of Egfr from podocytes protects from RPGN(a) Albuminuria (b) blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice, 8 days after NTS-induced RPGN (P<0.05 for all comparisons). (d) Survival curve of challenged Pod-Tet on-Cre EgfrloxP/loxP and littermate control mice in a severe model of RPGN. (* P<0.01). (e) Ultrastructural analysis of podocytes by transmission electron microscopy in NTS-treated Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice. More severe foot process effacement and irregular thickening of the GBM is visible in Pod-Tet on-Cre Egfrwt/wt animals. Scale bars: upper panels 2μm, lower panels 1μm.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: Selective deletion of Egfr from podocytes protects from RPGN(a) Albuminuria (b) blood urea nitrogen concentration and (c) proportion of crescentic glomeruli in Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice, 8 days after NTS-induced RPGN (P<0.05 for all comparisons). (d) Survival curve of challenged Pod-Tet on-Cre EgfrloxP/loxP and littermate control mice in a severe model of RPGN. (* P<0.01). (e) Ultrastructural analysis of podocytes by transmission electron microscopy in NTS-treated Pod-Tet on-Cre Egfrwt/wt and Pod-Tet on-Cre EgfrloxP/loxP mice. More severe foot process effacement and irregular thickening of the GBM is visible in Pod-Tet on-Cre Egfrwt/wt animals. Scale bars: upper panels 2μm, lower panels 1μm.
Mentions: To determine if EGFR expression in podocytes in vivo is necessary for crescent formation and renal failure, we selectively deleted Egfr from renal podocytes. We used a conditional expression model (Tet-On system) in which the target gene is deleted only in the presence of a tetracycline derivative to achieve temporal podocyte specific deletion of the Egfr gene in mice (Supplementary Fig. 5a,b). Mice of all genotypes were born at the expected Mendelian frequency and appeared healthy. Ten weeks after doxycyline administration, kidney histology was normal (Supplementary Fig. 5c), no apoptotic cells were observed in glomeruli (Supplementary Fig. 5d), and albuminuria was within physiological range (not shown). Ten Podocin-rtTA-Tet-O-Cre EgfrloxP/loxP males and 12 Podocin-rtTA-Tet-O-Cre Egfrwt/wt gender-matched littermates were subjected to severe, life-threatening RPGN with high dose NTS. Podocyte specific deletion of Egfr alleviated albumin urinary excretion (P<0.05) (Fig. 4a), the rise of BUN (P<0.05) (Fig. 4b), and crescent formation (P<0.05) (Fig. 4c) and completely protected mice from death (0% mortality vs. 66% mortality for control mice with unperturbed EGFR expression in podocytes; P<0.01; Fig. 4d). Improved kidney function and survival also correlated with less severe changes to podocyte ultrastructure in tetracycline induced Podocin-rtTA-Tet-O-Cre EgfrloxP/loxP mice relative to tetracycline induced Podocin-rtTA-Tet-O-Cre Egfrwt/wt littermate controls (Fig. 4e).

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