Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis.
Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis.
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DOI：
10.1038/srep42114
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发表时间：
2017-02-13
影响因子：
4.6
通讯作者：
Yokoi H
中科院分区：
文献类型：
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作者：
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
结缔组织生长因子（CTGF）协调生长因子的信号传导并促进纤维化。系统性CTGF敲除（KO）小鼠的新生儿死亡阻碍了成人肾脏疾病中CTGF的分析。本研究建立了3种CTGF条件性KO（cKO）小鼠模型，以探讨CTGF在抗肾小球基底膜（GBM）肾炎中的作用及来源。他莫昔芬诱导的全身性CTGF（Rosa-CTGF）cKO小鼠在诱导后表现出抗GBM肾炎中蛋白尿减少，新月体形成和系膜扩张改善。尽管足细胞以基础水平表达CTGF，但足细胞特异性CTGF（pod-CTGF）cKO小鼠在肾损伤中未显示出改善。相比之下，PDGFRα启动子驱动的CTGF（Pdgfra-CTGF）cKO小鼠主要缺乏系膜细胞的CTGF表达，表现出蛋白尿减少，组织学变化改善。在Rosa-CTGF cKO和Pdgfra-CTGF cKO小鼠中，肾小球巨噬细胞积聚、Adgre 1和Ccl 2表达以及M1/M2巨噬细胞比率均降低，但在pod-CTGF cKO小鼠中不降低。TGF-β1刺激的系膜细胞Ccl 2表达上调和巨噬细胞与活化系膜细胞的粘附通过CTGF的减少而减少。这些结果揭示了一种新的机制，巨噬细胞迁移到肾小球肾炎介导的CTGF来源于肾小球系膜细胞，暗示治疗潜力的CTGF抑制肾小球肾炎。
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.