Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose.
Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose.
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DOI：
10.1007/s10157-005-0347-x
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发表时间：
2005-06-01
影响因子：
2.3
通讯作者：
Suzuki, Hiromichi
中科院分区：
文献类型：
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作者：
Kobayashi, Tatsuya;Inoue, Tsutomu;Suzuki, Hiromichi
背景：据报道，结缔组织生长因子（CTGF）在糖尿病肾小管上皮细胞中表达。除其他因子外，CTGF介导了转化生长因子- β (tgf - β)的下游纤维化作用，但其在糖尿病肾间质纤维化中的确切作用尚不清楚。方法：我们采用一种共培养系统，包括培养的小鼠近端小管上皮细胞（mProx24）和肾成纤维细胞（TFB），作为肾脏上皮下间质模型，以检测mProx24细胞衍生的CTGF对高葡萄糖（30 mM）的促纤维化作用。结果：我们发现葡萄糖在培养的mProx24中以剂量和时间依赖的方式刺激CTGF表达，并且这种作用是通过tgf - β水平的增加介导的。我们还发现，高葡萄糖显著刺激TFB细胞产生促纤维化分子，如I型胶原蛋白、纤连蛋白EIIIA异构体和纤溶酶原激活物抑制剂-1。这些分子的诱导既有直接的，也有间接的，后者的诱导由mProx24细胞衍生的CTGF介导，而CTGF又由mProx24细胞产生的tgf - β诱导。结论：CTGF在高糖应激下介导肾间质纤维化中发挥重要作用，是抗纤维化治疗的合理靶点。
BACKGROUND: It was reported that connective tissue growth factor (CTGF) was expressed in the tubular epithelial cells of the diabetic kidney. CTGF has, among other factors, been implicated in mediating the downstream, profibrotic effects of transforming growth factor-beta (TGF-beta), though is precise role in interstitial fibrogenesis in the diabetic kidney has not yet been clarified.METHODS: We employed a coculture system involving cultured murine proximal tubular epithelial cells (mProx24) and renal fibroblasts (TFB), as a model of the subepithelial mesenchyme in the kidney in order to examine the profibrotic effects of CTGF derived from mProx24 cells in response to high glucose (30 mM).RESULTS: We showed that glucose stimulated CTGF expression in cultured mProx24 in both a dose- and a time-dependent manner, and that this effect was mediated by increased levels of TGF-beta. We also found that high glucose significantly stimulated TFB cells to produce profibrotic molecules, such as type I collagen, the EIIIA isoform of fibronectin, and plasminogen activator inhibitor-1. The induction of these molecules was both direct and indirect, the latter induction being mediated by mProx24 cell-derived CTGF, which, in turn, was induced by TGF-beta that was produced by the mProx24 cells.CONCLUSIONS: CTGF plays an important role in mediating renal interstitial fibrogenesis in response to high glucose and, as such, is a reasonable target for anti-fibrotic therapy.