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首页> 外文期刊>Scientific reports. >Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis
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Crucial Role of Mesangial Cell-derived Connective Tissue Growth Factor in a Mouse Model of Anti-Glomerular Basement Membrane Glomerulonephritis

机译：Mesangial细胞衍生的结缔组织生长因子在抗肾小球基底膜肾小球肾小球肾炎小鼠模型中的关键作用

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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.
机译：结缔组织生长因子（CTGF）坐标生长因子的信号传导，促进纤维化。全身性CTGF淘汰赛（KO）小鼠的新生儿死亡在成人肾病中阻碍了CTGF的分析。我们建立了3种CTGF条件KO（CKO）小鼠，探讨了抗肾小球基底膜（GBM）肾小球肾炎CTGF的作用和来源。 Tamoxifen-Invucible Systemic CTGF（ROSA-CTGF）CKO小鼠在诱导后呈现出改善的新月形形成和抗GBM肾炎中的患有患病性的蛋白尿和患有患病症。虽然CTGF由基底水平的哆哆ytes表示，但是肾小型细胞特异性CTGF（POD-CTGF）CKO小鼠显示出肾损伤没有改善。相反，PDGFRα启动子驱动的CTGF（PDGFRA-CTGF）CKO小鼠主要缺乏Mesangial细胞表达CTGF表达，随着改善的组织学变化表现出降低的蛋白尿。肾小球巨噬细胞累积，Adgre1和CCl2的表达，以及M​​1 / M2巨噬细胞的比例在ROSA-CTGF CKO和PDGFRA-CTGF CKO小鼠中都减少，但不在Pod-CTGF CKO小鼠中减少。通过减少CTGF降低了乳腺细胞中的TGF-β1刺激的乳腺细胞和巨噬细胞粘附对活性的椎间囊细胞的粘性。这些结果揭示了一种新的巨噬细胞迁移到肾小球与由患有Mesangial细胞介导的肾炎的肾炎，暗示CTGF抑制在肾小球肾炎中的治疗潜力。

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