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: Naohiro Toda, Kiyoshi Mori, Masato Kasahara, Akira Ishii, Kenichi Koga, Shoko Ohno, Keita P Mori, Yukiko Kato, Keisuke Osaki, Takashige Kuwabara, Katsutoshi Kojima, Daisuke Taura, Masakatsu Sone, Taiji Matsusaka, Kazuwa Nakao, Masashi Mukoyama, Motoko Yanagita, Hideki Yokoi
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 42114 (02 13 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28191821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Connective Tissue Growth Factor

Topics

• Animals
• Cell Adhesion
• Cell Movement
• Connective Tissue Growth Factor (genetics, metabolism)
• Glomerular Basement Membrane (immunology)
• Glomerulonephritis, Membranoproliferative (pathology)
• Macrophages (immunology)
• Mesangial Cells (metabolism)
• Mice
• Mice, Knockout