Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis
Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis
复制标题
DOI：
10.1681/asn.2004040339
复制
发表时间：
2005-01-01
影响因子：
13.6
通讯作者：
Suzuki, H
中科院分区：
文献类型：
--
作者：
Okada, H;Kikuta, T;Suzuki, H
结缔组织生长因子 (CTGF) 被认为是介导 TGF-β 下游促纤维化作用的候选因子之一。然而，其在肾间质纤维发生中的确切作用尚未阐明。先前已证明，在肾次全切除术（SNx）模型的残肾中，CTGF 在被间质纤维化吞噬的肾小管上皮细胞中表达。在本研究中，模拟肾脏上皮下间质的肾小管上皮细胞 (mProx24) 和肾小管间质成纤维细胞 (TFB) 的共培养物被用来研究 TGF-β1 诱导的 CTGF 的促纤维化作用。在这些共培养物中，TGF-β1 处理导致 TFB 中 I 型胶原和纤连蛋白的 mRNA 水平显着增加。这些影响既有直接的，也有间接的，后者是由源自共培养的 mProx24 的 CTGF 介导的。然后对TGF-β1转基因小鼠进行肾大部切除并用CTGF反义寡脱氧核苷酸处理，并分析其肾脏的纤维化情况。尽管 TGF-β1 mRNA 水平持续存在，静脉注射 CTGF 反义寡脱氧核苷酸仍显着阻断这些动物残肾近端肾小管上皮细胞中 CTGF 的表达。 CTGF mRNA 水平的降低与基质分子以及蛋白酶抑制剂纤溶酶原激活物抑制剂 1 和金属蛋白酶组织抑制剂 1 的 mRNA 水平降低同时发生，从而抑制肾间质纤维化。总之，肾小管 CTGF 作为残肾中 TGF-β1 促纤维化作用的下游介质，是设计用于治疗 TGF-β1 依赖性间质纤维化的抗纤维化药物的一个有前景的靶点。
Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-beta. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-beta1-induced CTGF. In these co-cultures, TGF-beta1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-beta1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-beta1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-beta1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-beta1- dependent interstitial fibrosis.