title: Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis.
abstract: Connective tissue growth factor (CTGF) coordinates the signaling of growth factors and promotes fibrosis. Neonatal death of systemic CTGF knockout (KO) mice has hampered analysis of CTGF in adult renal diseases. We established 3 types of CTGF conditional KO (cKO) mice to investigate a role and source of CTGF in anti-glomerular basement membrane (GBM) glomerulonephritis. Tamoxifen-inducible systemic CTGF (Rosa-CTGF) cKO mice exhibited reduced proteinuria with ameliorated crescent formation and mesangial expansion in anti-GBM nephritis after induction. Although CTGF is expressed by podocytes at basal levels, podocyte-specific CTGF (pod-CTGF) cKO mice showed no improvement in renal injury. In contrast, PDGFRα promoter-driven CTGF (Pdgfra-CTGF) cKO mice, which predominantly lack CTGF expression by mesangial cells, exhibited reduced proteinuria with ameliorated histological changes. Glomerular macrophage accumulation, expression of Adgre1 and Ccl2, and ratio of M1/M2 macrophages were all reduced both in Rosa-CTGF cKO and Pdgfra-CTGF cKO mice, but not in pod-CTGF cKO mice. TGF-β1-stimulated Ccl2 upregulation in mesangial cells and macrophage adhesion to activated mesangial cells were decreased by reduction of CTGF. These results reveal a novel mechanism of macrophage migration into glomeruli with nephritis mediated by CTGF derived from mesangial cells, implicating the therapeutic potential of CTGF inhibition in glomerulonephritis.
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Toda
authors.affiliation: School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.|Department of Nephrology and Kidney Research, Shizuoka General Hospital, Shizuoka, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Mori
authors.affiliation: Institute for Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kasahara
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Koga
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Keita P
authors.initials: KP
authors.lastname: Mori
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Osaki
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.|Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Takashige
authors.initials: T
authors.lastname: Kuwabara
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japa.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japa.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Taura
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japa.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.|Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mukoyama
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Yanagita
authors.affiliation: Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Yokoi
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D050533:Glomerular Basement Membrane / Q000276:immunology*; D015432:Glomerulonephritis, Membranoproliferative / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D055513:Connective Tissue Growth Factor