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Christos Chatziantoniou - One of the best experts on this subject based on the ideXlab platform.

  • periostin and Discoidin Domain Receptor 1 new biomarkers or targets for therapy of renal disease
    Frontiers in Medicine, 2017
    Co-Authors: Niki Prakoura, Christos Chatziantoniou
    Abstract:

    Chronic kidney disease can be a life-threatening condition which eventually requires renal replacement therapy through dialysis or transplantation. A lot of effort and resources have been invested the last years in the identification of novel markers of progression and targets for therapy, in order to achieve a more efficient prognosis, diagnosis and treatment of renal diseases. Using experimental models of renal disease, we identified and studied two promising candidates: periostin, a matricellular protein with high expression in bone and dental tissues, and Discoidin Domain Receptor 1 (DDR1), a transmembrane collagen Receptor of the tyrosine kinase family. Both proteins are inactive in physiological conditions, while they are highly up-regulated during development of renal disease and are primarily expressed at the sites of injury. Further studies demonstrated that both periostin and DDR1 are involved in the regulation of inflammation and fibrosis, two major processes implicated in the development of renal disease. Targeting of either protein by genetic deletion or pharmaco-genetic inhibition via antisense oligonucleotides highly attenuates renal damage and preserves renal structure and function in several animal models. The scope of this review is to summarize the existing evidence supporting the role of periostin and DDR1 as novel biomarkers and therapeutic targets in chronic kidney disease.

  • Periostin and Discoidin Domain Receptor 1: New Biomarkers or Targets for Therapy of Renal Disease
    Frontiers Media S.A., 2017
    Co-Authors: Niki Prakoura, Christos Chatziantoniou
    Abstract:

    Chronic kidney disease (CKD) can be a life-threatening condition, which eventually requires renal replacement therapy through dialysis or transplantation. A lot of effort and resources have been invested the last years in the identification of novel markers of progression and targets for therapy, in order to achieve a more efficient prognosis, diagnosis, and treatment of renal diseases. Using experimental models of renal disease, we identified and studied two promising candidates: periostin, a matricellular protein with high expression in bone and dental tissues, and Discoidin Domain Receptor 1 (DDR1), a transmembrane collagen Receptor of the tyrosine kinase family. Both proteins are inactive in physiological conditions, while they are highly upregulated during development of renal disease and are primarily expressed at the sites of injury. Further studies demonstrated that both periostin and DDR1 are involved in the regulation of inflammation and fibrosis, two major processes implicated in the development of renal disease. Targeting of either protein by genetic deletion or pharmacogenetic inhibition via antisense oligonucleotides highly attenuates renal damage and preserves renal structure and function in several animal models. The scope of this review is to summarize the existing evidence supporting the role of periostin and DDR1 as novel biomarkers and therapeutic targets in CKD

  • Protective effects of genetic inhibition of Discoidin Domain Receptor 1 in experimental renal disease
    Scientific Reports, 2016
    Co-Authors: Monique Kerroch, Jean-jacques Boffa, Christos Chatziantoniou, Carlo Alfieri, Aude Dorison, Jean Claude Dussaule
    Abstract:

    Chronic kidney disease is a progressive incurable pathology affecting millions of people. Intensive investigations aim to identify targets for therapy. We have previously demonstrated that abnormal expression of the Discoidin Domain Receptor 1 (DDR1) is a key factor of renal disease by promoting inflammation and fibrosis. The present study investigates whether blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology. Severe renal disease was induced by either injecting nephrotoxic serum (NTS) or performing unilateral ureteral obstruction in mice, and the expression of DDR1 was inhibited by administering antisense oligodeoxynucleotides either at 4 or 8 days after NTS (corresponding to early or more established phases of disease, respectively), or at day 2 after ligation. DDR1 antisense administration at day 4 stopped the increase of proteinuria and protected animals against the progression of glomeruloneprhitis, as evidenced by functional, structural and cellular indexes. Antisense administration at day 8 delayed progression –but to a smaller degree- of renal disease. Similar beneficial effects on renal structure and inflammation were observed with the antisense administration of DDR1 after ureteral ligation. Thus, targeting DDR1 can be a promising strategy in the treatment of chronic kidney disease.

  • Discoidin Domain Receptor 1 and periostin new players in chronic kidney disease
    Nephrology Dialysis Transplantation, 2015
    Co-Authors: Carlo Alfieri, Panagiotis Kavvadas, Paola Simonini, Masami Ikehata, Jean Claude Dussaule, Christos E Chadjichristos, Maria Pia Rastaldi, Piergiorgio Messa, Christos Chatziantoniou
    Abstract:

    Theincidence andprevalenceofchronickidneydiseaserepresents an important problem for public health. In renal diseases, the main histologic alterations derive from the development of renal fibrosis which results from the loss of the balance between proand anti-fibrotic factors. Tyrosine kinase Receptors (RTKs) and matricellular proteins (MPs) are nowadays studied as potential modulators of renal injury. RTKs regulate cell cycle, migration, metabolism and cellular differentiation. Discoidin Domain Receptor-1 (DDR-1) is an RTK that has been extensively studied in cancer, and lung and renal diseases. It modulates inflammatory recruitment, extracellular matrix deposition and fibrosis; in renal diseases, it appears to act independently of the underlying disease. MPs regulate cell-matrix interactions and matrix accumulation, cellular adhesion and migration, and expression of inflammatory cells. Periostin is an MP, mainly studied in bone, heart, lung and cancer. Several studies demonstrated that it mediates cellmatrix interactions, migration of inflammatory cells and development of fibrosis. Recently, it has been reported in several nephropathies. In this review, we discuss the potential pathological roles of DDR-1 and periostin focussing on the kidney in both experimental models and human diseases.

  • Genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis.
    FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard, Chantal Jouanneau, Eric Rondeau, Pierre Ronco, Jean-jacques Boffa, Christos Chatziantoniou
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P

Wolfgang Vogel - One of the best experts on this subject based on the ideXlab platform.

  • Discoidin Domain Receptor 1 deficient mice are resistant to bleomycin induced lung fibrosis
    American Journal of Respiratory and Critical Care Medicine, 2006
    Co-Authors: Carmel Avivigreen, Mayank Singal, Wolfgang Vogel
    Abstract:

    Rationale: Discoidin Domain Receptor 1 (DDR1) is a tyrosine kinase activated by native collagens. Based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 mediates disease progression after lung injury.Objectives: To investigate the inflammatory and fibrotic responses of DDR1 knockout and wild-type mice to bleomycin-induced lung injury.Methods: Age- and sex-matched DDR1 knockout and wild-type C57BL/6 mice received a single intratracheal instillation of 2 U/kg bleomycin or saline, respectively. After 2 wk, lung inflammation and fibrosis were assessed using immunohistochemistry, real-time polymerase chain reaction, TUNEL assay, ELISA, fluorescence-activated cell sorting, and Western blot analysis.Measurements and Main Results: Compared with wild-type animals, DDR1-null mice were largely protected against bleomycin-induced injury. Bleomycin-induced increases in collagen protein levels and tenascin-...

  • sensing extracellular matrix an update on Discoidin Domain Receptor function
    Cellular Signalling, 2006
    Co-Authors: Wolfgang Vogel, Rahim Abdulhussein, Caroline E Ford
    Abstract:

    Discoidin Domain Receptors (DDRs) have recently emerged as non-integrin-type Receptors for collagen. The two mammalian gene products Discoidin Domain Receptor 1 and -2 constitute a subfamily of tyrosine kinase Receptors that are selectively expressed in a number of different cell types and organs. Upon collagen activation, DDRs regulate cell adhesion, proliferation and extracellular matrix remodeling. Here we review the various signaling pathways and cellular responses evoked by activated DDRs. Additionally, we give an overview of the more recent advances in understanding the role of DDRs in various human diseases, in particular during tumor progression, atherosclerosis, inflammation and tissue fibrosis. Furthermore, we discuss potential roles of genes homologous to mammalian DDRs identified in flies, worms and sponges. We show that the structural organization of these DDR-related genes is highly conserved throughout evolution suggesting that invertebrate DDRs may also function as Receptors for collagen. By highlighting current questions about these unusual collagen Receptors, we hope to attract new research on DDRs from a variety of different fields.

  • Expression of Discoidin Domain Receptor 1 during mouse brain development follows the progress of myelination.
    Neuroscience, 2006
    Co-Authors: Neus Franco-pons, C. Virgos, Jesús M. Ureña, Eduardo Soriano, Wolfgang Vogel, Elisabet Vilella
    Abstract:

    Discoidin Domain Receptor 1 is a tyrosine kinase Receptor expressed in a variety of tissues including the brain. This study describes mRNA and protein expression of Discoidin Domain Receptor 1 in mouse brain during development and provides new insights into its role during gliogenesis and neurogenesis. We performed in situ hybridization for Discoidin Domain Receptor 1 in mouse brains at embryonic day 18, postnatal days 5, 9, 15, 21 and adulthood and observed a diffuse pattern in the proliferative areas during embryogenesis. From postnatal day 5 onwards, a defined cellular expression pattern of Discoidin Domain Receptor 1 was observed, mainly located in white matter tracts and following a spatio-temporal pattern that overlapped the progress of myelination. Next, we performed double-labeling reactions (in situ hybridization followed by immunohistochemistry) that confirmed that Discoidin Domain Receptor 1 was expressed by mature oligodendrocytes. We observed that cells positive for Discoidin Domain Receptor 1 also expressed carnosine and anti-adenomatous polyposis coli, two mature oligodendrocyte markers. Based on the localization of Discoidin Domain Receptor 1 specifically in the white matter fiber tracts during postnatal development, we suggest that Discoidin Domain Receptor 1 participates in the development and maintenance of the myelin sheath.

  • expression and signaling activity of wnt 5a Discoidin Domain Receptor 1 and syk plays distinct but decisive roles in breast cancer patient survival
    Clinical Cancer Research, 2005
    Co-Authors: Janna Dejmek, Karin Leandersson, Stefan O Emdin, Jonas Manjer, Anders Bjartell, Wolfgang Vogel, Göran Landberg, Tommy Andersson
    Abstract:

    Expression and signaling activity of Wnt-5a/Discoidin Domain Receptor-1 and Syk plays distinct but decisive roles in breast cancer patient survival.

  • Ligand-induced shedding of Discoidin Domain Receptor 1
    FEBS Letters, 2002
    Co-Authors: Wolfgang Vogel
    Abstract:

    Tyrosine kinases belonging to the Discoidin Domain Receptor (DDR) family are activated upon stimulation with various types of collagen. In response to collagen treatment, immunoprecipitation of DDR1 with an antibody specific to the juxtamembrane region results in co-purification of a previously unrecognized tyrosine phosphorylated protein of 62 kDa molecular weight. Here, this protein is identified as C-terminal cleavage product of the full-length DDR1 Receptor and a DDR1-specific shedding enzyme postulated. Shedding of DDR1 can be partially blocked by the furin inhibitor decanoyl-RVKR-chloromethylketone and completely inhibited by the hydroxamate-based inhibitor batimastat. The characteristic of the DDR1 sheddase to be blocked by batimastat suggests that it belongs to the membrane-bound matrix metalloproteinase or disintegrin and metalloproteinase family of proteases.

Kimiyoshi Arimura - One of the best experts on this subject based on the ideXlab platform.

  • Letter of retraction: Suppression of Discoidin Domain Receptor 1 by RNA interference attenuates lung inflammation.
    Journal of Immunology, 2008
    Co-Authors: Masaki Watanabe, Yuko Shirahama, Ryuki Hirano, Hideo Mitsuyama, Ikkou Higashimoto, Mitsuhiro Osame, Kimiyoshi Arimura
    Abstract:

    We wish to retract the article titled “Suppression of Discoidin Domain Receptor 1 by RNA Interference Attenuates Lung Inflammation” by Wataru Matsuyama, Masaki Watanabe, Yuko Shirahama, Ryuki Hirano, Hideo Mitsuyama, Ikkou Higashimoto, Mistuhiro Osame, and Kimiyoshi Arimura, [ The Journal of

  • Retraction: Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Fibrosis
    Journal of immunology (Baltimore Md. : 1950), 2008
    Co-Authors: Masaki Watanabe, Yuko Shirahama, Kimiyoshi Arimura, Ikkou Higashimoto, Mitsuhiro Osame, Ken-ichi Oonakahara, Teizo Yoshimura
    Abstract:

    We wish to retract the article titled “Activation of Discoidin Domain Receptor 1 on CD14-Positive Bronchoalveolar Lavage Fluid Cells Induces Chemokine Production in Idiopathic Pulmonary Fibrosis” by Wataru Matsuyama, Masaki Watanabe, Yuko Shirahama, Ken-ichi Oonakahara, Ikkou Higashimoto, Teizo

  • Involvement of Discoidin Domain Receptor 1 in the Deterioration of Pulmonary Sarcoidosis
    American Journal of Respiratory Cell and Molecular Biology, 2005
    Co-Authors: Wataru Matsuyama, Yuko Shirahama, Hideo Mitsuyama, Ikkou Higashimoto, Masaki Watanabe, Mitsuhiro Osame, Kimiyoshi Arimura
    Abstract:

    The prognosis of sarcoidosis with pulmonary infiltrates differs in each case, and several cytokines are reported to contribute to its deterioration. However, the detailed mechanism has not been fully elucidated. Discoidin Domain Receptor 1 (DDR1) is a Receptor tyrosine kinase activated by collagen and associated with cytokine production from inflammatory cells. We previously reported the functional expression of DDR1 on CD14-positive bronchoalveolar lavage fluid (BALF) cells in vivo. In this study, we hypothesized that DDR1 might be associated with the deterioration of pulmonary sarcoidosis (PS), and investigated 33 patients with sarcoidosis with pulmonary infiltrates, prospectively. We found that patients with deteriorated PS showed significantly higher DDR1 expression in CD14-positive BALF cells predominant with DDR1b isoforms. Activation of DDR1 induced monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) production in a p38 mitogen-activated protein kinase–dependent manner...

  • Involvement of Discoidin Domain Receptor 1 in the deterioration of pulmonary sarcoidosis.
    American journal of respiratory cell and molecular biology, 2005
    Co-Authors: Wataru Matsuyama, Yuko Shirahama, Hideo Mitsuyama, Ikkou Higashimoto, Masaki Watanabe, Mitsuhiro Osame, Kimiyoshi Arimura
    Abstract:

    The prognosis of sarcoidosis with pulmonary infiltrates differs in each case, and several cytokines are reported to contribute to its deterioration. However, the detailed mechanism has not been fully elucidated. Discoidin Domain Receptor 1 (DDR1) is a Receptor tyrosine kinase activated by collagen and associated with cytokine production from inflammatory cells. We previously reported the functional expression of DDR1 on CD14-positive bronchoalveolar lavage fluid (BALF) cells in vivo. In this study, we hypothesized that DDR1 might be associated with the deterioration of pulmonary sarcoidosis (PS), and investigated 33 patients with sarcoidosis with pulmonary infiltrates, prospectively. We found that patients with deteriorated PS showed significantly higher DDR1 expression in CD14-positive BALF cells predominant with DDR1b isoforms. Activation of DDR1 induced monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) production in a p38 mitogen-activated protein kinase-dependent manner from CD14-positive BALF cells of patients with deteriorated sarcoidosis. DDR1 activation also induced NF-kappaB nuclear translocation in CD14-positive BALF cells of patients with deteriorated PS. The inhibitor of NF-kappaB inhibited the production of MCP-1 and MMP-9. We propose that DDR1 is associated with the deterioration of pulmonary sarcoidosis.

Monique Kerroch - One of the best experts on this subject based on the ideXlab platform.

  • Protective effects of genetic inhibition of Discoidin Domain Receptor 1 in experimental renal disease
    Scientific Reports, 2016
    Co-Authors: Monique Kerroch, Jean-jacques Boffa, Christos Chatziantoniou, Carlo Alfieri, Aude Dorison, Jean Claude Dussaule
    Abstract:

    Chronic kidney disease is a progressive incurable pathology affecting millions of people. Intensive investigations aim to identify targets for therapy. We have previously demonstrated that abnormal expression of the Discoidin Domain Receptor 1 (DDR1) is a key factor of renal disease by promoting inflammation and fibrosis. The present study investigates whether blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology. Severe renal disease was induced by either injecting nephrotoxic serum (NTS) or performing unilateral ureteral obstruction in mice, and the expression of DDR1 was inhibited by administering antisense oligodeoxynucleotides either at 4 or 8 days after NTS (corresponding to early or more established phases of disease, respectively), or at day 2 after ligation. DDR1 antisense administration at day 4 stopped the increase of proteinuria and protected animals against the progression of glomeruloneprhitis, as evidenced by functional, structural and cellular indexes. Antisense administration at day 8 delayed progression –but to a smaller degree- of renal disease. Similar beneficial effects on renal structure and inflammation were observed with the antisense administration of DDR1 after ureteral ligation. Thus, targeting DDR1 can be a promising strategy in the treatment of chronic kidney disease.

  • Genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis.
    FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard, Chantal Jouanneau, Eric Rondeau, Pierre Ronco, Jean-jacques Boffa, Christos Chatziantoniou
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P

  • genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis
    The FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P<0.05). Reciprocal stimulation between DDR1 and interleukin-1b expression in vivo and in cultured podocytes suggested a positive feed-back loop between DDR1 and inflammation. In NTS-treated WT mice, administration of DDR1-specific ...

  • genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis
    The FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P<0.05). Reciprocal stimulation between DDR1 and interleukin-1b expression in vivo and in cultured podocytes suggested a positive feed-back loop between DDR1 and inflammation. In NTS-treated WT mice, administration of DDR1-specific antisense oligodeoxynucleotides decreased DDR1 expression (-56%) and protected renal function and structure, including nephrin expression (4.2±1.4 vs. 0.9±0.4 arbitrary units, P<0.05), compared to control mice receiving scrambled oligodeoxynucleotides. The therapeutic potential of this approach was reinforced by the observation of increased DDR1 expression in glomeruli of patients with lupus nephritis and Goodpasture's syndrome. These results prompt further interest in DDR1 blockade strategies, especially in the treatment of glomerulonephritis.

Laurent Mesnard - One of the best experts on this subject based on the ideXlab platform.

  • Genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis.
    FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard, Chantal Jouanneau, Eric Rondeau, Pierre Ronco, Jean-jacques Boffa, Christos Chatziantoniou
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P

  • genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis
    The FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P<0.05). Reciprocal stimulation between DDR1 and interleukin-1b expression in vivo and in cultured podocytes suggested a positive feed-back loop between DDR1 and inflammation. In NTS-treated WT mice, administration of DDR1-specific ...

  • genetic inhibition of Discoidin Domain Receptor 1 protects mice against crescentic glomerulonephritis
    The FASEB Journal, 2012
    Co-Authors: Monique Kerroch, Dominique Guerrot, Sophie Vandermeersch, Sandrine Placier, Laurent Mesnard
    Abstract:

    This study investigated the role of Discoidin Domain Receptor 1 (DDR1), a collagen Receptor that displays tyrosine-kinase activity, in the development of glomerulonephritis. Crescentic glomerulonephritis was induced in DDR1-deficient mice and their wild-type (WT) littermates as controls, by injection of alloimmune sheep nephrotoxic serum (NTS). Histological, functional and transcriptomic studies were performed. Glomerulonephritis produced a 17-fold increase of DDR1 expression, predominantly in glomeruli. DDR1 deletion protected NTS-treated mice against glomerular disease (proteinuria/creatininuria 5.5±1.1 vs. 13.2±0.8 g/mmol in WT, crescents 12±2 vs. 24±2% of glomeruli, urea 16±2 vs. 28±5 mM), hypertension (123±11 vs. 157±8 mmHg), and premature death (70 vs. 10% survival) (all P<0.05). Reciprocal stimulation between DDR1 and interleukin-1b expression in vivo and in cultured podocytes suggested a positive feed-back loop between DDR1 and inflammation. In NTS-treated WT mice, administration of DDR1-specific antisense oligodeoxynucleotides decreased DDR1 expression (-56%) and protected renal function and structure, including nephrin expression (4.2±1.4 vs. 0.9±0.4 arbitrary units, P<0.05), compared to control mice receiving scrambled oligodeoxynucleotides. The therapeutic potential of this approach was reinforced by the observation of increased DDR1 expression in glomeruli of patients with lupus nephritis and Goodpasture's syndrome. These results prompt further interest in DDR1 blockade strategies, especially in the treatment of glomerulonephritis.