title: Connective Tissue Growth Factor Domain 4 Amplifies Fibrotic Kidney Disease through Activation of LDL Receptor-Related Protein 6.
abstract: Connective tissue growth factor (CTGF), a matrix-associated protein with four distinct cytokine binding domains, has roles in vasculogenesis, wound healing responses, and fibrogenesis and is upregulated in fibroblasts and myofibroblasts in disease. Here, we investigated the role of CTGF in fibrogenic cells. In mice, tissue-specific inducible overexpression of CTGF by kidney pericytes and fibroblasts had no bearing on nephrogenesis or kidney homeostasis but exacerbated inflammation and fibrosis after ureteral obstruction. These effects required the WNT receptor LDL receptor-related protein 6 (LRP6). Additionally, pericytes isolated from these mice became hypermigratory and hyperproliferative on overexpression of CTGF. CTGF is cleavedin vivointo distinct domains. Treatment with recombinant domain 1, 1+2 (N terminus), or 4 (C terminus) independently activated myofibroblast differentiation and wound healing responses in cultured pericytes, but domain 4 showed the broadest profibrotic activity. Domain 4 exhibited low-affinity binding to LRP6 inin vitrobinding assays, and inhibition of LRP6 or critical signaling cascades downstream of LRP6, including JNK and WNT/β-catenin, inhibited the biologic activity of domain 4. Administration of blocking antibodies specifically against CTGF domain 4 or recombinant Dickkopf-related protein-1, an endogenous inhibitor of LRP6, effectively inhibited inflammation and fibrosis associated with ureteral obstructionin vivoTherefore, domain 4 of CTGF and the WNT signaling pathway are important new targets in fibrosis.
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.|Division of Nephrology, Departments of Medicine and.|Pathology and.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Bryce G
authors.initials: BG
authors.lastname: Johnson
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts; shuyu.ren@biogen.com jeremysd@u.washington.edu.|Division of Nephrology, Departments of Medicine and.|Pathology and.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Ren
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Gamze
authors.initials: G
authors.lastname: Karaca
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.|Division of Nephrology, Departments of Medicine and.|Pathology and.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Ivan G
authors.initials: IG
authors.lastname: Gomez
authors.affiliation: Division of Nephrology, Departments of Medicine and.|Pathology and.
authors.forename: Cécile
authors.initials: C
authors.lastname: Fligny
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Smith
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergun
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: George
authors.initials: G
authors.lastname: Locke
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Benbo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hayes
authors.affiliation: Boehringer Ingelheim, Ridgefield, Connecticut.
authors.forename: Scott
authors.initials: S
authors.lastname: MacDonnell
authors.affiliation: Research and Development, Biogen, Cambridge, Massachusetts; shuyu.ren@biogen.com jeremysd@u.washington.edu.|Division of Nephrology, Departments of Medicine and.|Pathology and.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; and.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D000818:Animals; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D005347:Fibroblasts; D005355:Fibrosis / Q000209:etiology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020286:Pericytes
chemical_list: C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D055513:Connective Tissue Growth Factor
keywords: Connective Tissue Growth Factor; DKK1; LRP6; fibrosis; inflammation; pericytes