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2017 ; 7
(ä): 42114
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Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse
Model of Anti-Glomerular Basement Membrane Glomerulonephritis
#MMPMID28191821
Toda N
; Mori K
; Kasahara M
; Ishii A
; Koga K
; Ohno S
; Mori KP
; Kato Y
; Osaki K
; Kuwabara T
; Kojima K
; Taura D
; Sone M
; Matsusaka T
; Nakao K
; Mukoyama M
; Yanagita M
; Yokoi H
Sci Rep
2017[Feb]; 7
(ä): 42114
PMID28191821
show ga
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, PDGFR?
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-?1-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.