Format

Send to

Choose Destination
Sci Rep. 2017 Feb 13;7:42114. doi: 10.1038/srep42114.

Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis.

Author information

1
Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto Japan.
2
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
3
Department of Nephrology and Kidney Research, Shizuoka General Hospital, Shizuoka, Japan.
4
Institute for Clinical and Translational Science, Nara Medical University Hospital, Kashihara, Japan.
5
Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
6
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japa.
7
Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Japan.
8
Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto Japan.

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.

PMID:
28191821
PMCID:
PMC5304211
DOI:
10.1038/srep42114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center