title: Genetic inhibition of discoidin domain receptor 1 protects mice against crescentic glomerulonephritis.
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.
authors: INSERM UMR S 702, Service de Néphrologie et Dialyses, Hôpital Tenon, Assistance Publique–Hôpitaux de Paris, Université Pierre et Marie Curie (UPMC), Paris 6 University, 75020 Paris, France.
authors: Monique
authors: M
authors: Kerroch
authors: Dominique
authors: D
authors: Guerrot
authors: Sophie
authors: S
authors: Vandermeersch
authors: Sandrine
authors: S
authors: Placier
authors: Laurent
authors: L
authors: Mesnard
authors: Chantal
authors: C
authors: Jouanneau
authors: Eric
authors: E
authors: Rondeau
authors: Pierre
authors: P
authors: Ronco
authors: Jean-Jacques
authors: JJ
authors: Boffa
authors: Christos
authors: C
authors: Chatziantoniou
authors: Jean-Claude
authors: JC
authors: Dussaule
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D000070818:Discoidin Domain Receptors; D005260:Female; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000235:genetics / Q000517:prevention & control* / Q000652:urine; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011507:Proteinuria / Q000235:genetics / Q000652:urine; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D011975:Receptors, Mitogen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases