title: Discoidin domain receptor 1 is a major mediator of inflammation and fibrosis in obstructive nephropathy.
abstract: The interactions between tubulointerstitial infiltrating cells and the extracellular matrix play an important role in regulating renal fibrosis. Discoidin domain receptor 1 (DDR1) is a nonintegrin tyrosine kinase receptor for collagen implicated in cell adhesion, proliferation, and extracellular matrix remodeling. We have previously demonstrated that transgenic mice lacking DDR1 are protected from hypertension-associated renal fibrosis. The purpose of this study was to determine the role of DDR1 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After 12 days of unilateral ureteral obstruction (UUO), kidney histopathologic and real-time quantitative PCR analyses were performed in DDR1(-/-) and wild-type mice. DDR1 expression was strongly increased in the obstructed kidney. Wild-type mice developed important perivascular and interstitial inflammation and fibrosis. In comparison, DDR1(-/-) mice displayed reduced accumulation of fibrillar collagen and transforming growth factor β expression. F4/80(+) cell count and proinflammatory cytokines were remarkably blunted in DDR1(-/-) obstructed kidneys. Leukocyte rolling and adhesion evaluated by intravital microscopy were not different between DDR1(-/-) and wild-type mice. Importantly, macrophages isolated from DDR1(-/-) mice presented similar M1/M2 polarization but displayed impaired migration in response to monocyte chemoattractant protein-1. Together, these data suggest that DDR1 plays an important role in the pathogenesis of renal disease via enhanced inflammation. Inhibition of DDR1 expression or activity may represent a novel therapeutic target against the progression of renal diseases.
authors.affiliation: INSERM UMR S 702, Hôpital Tenon, Paris, France; UPMC Paris 6 University, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guerrot
authors.forename: Monique
authors.initials: M
authors.lastname: Kerroch
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.forename: Claire
authors.initials: C
authors.lastname: Trivin
authors.forename: Mouna
authors.initials: M
authors.lastname: Mael-Ainin
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dussaule
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D000070819:Discoidin Domain Receptor 1; D005355:Fibrosis / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D007674:Kidney Diseases / Q000150:complications* / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*
chemical_list: C083249:Ddr1 protein, mouse; D000070819:Discoidin Domain Receptor 1; D020794:Receptor Protein-Tyrosine Kinases