Gremlin activates the Smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells.
Gremlin activates the Smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells.
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DOI：
10.1155/2014/802841
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发表时间：
2014
影响因子：
--
通讯作者：
Ruiz-Ortega M
中科院分区：
文献类型：
--
作者：
Rodrigues-Diez R;Rodrigues-Diez RR;Lavoz C;Carvajal G;Droguett A;Garcia-Redondo AB;Rodriguez I;Ortiz A;Egido J;Mezzano S;Ruiz-Ortega M
Gremlin是一种在人类慢性肾病和肾细胞中响应于转化生长因子-β（TGF-β）而上调的发育基因。上皮间质转化（EMT）是参与肾纤维化的一个过程。在肾小管上皮细胞中，我们最近描述了Gremlin诱导EMT并作为下游TGF-β介导剂。我们的目的是调查Gremlin是否通过调节Smad通路参与EMT。用Gremlin刺激人肾小管上皮细胞（HK 2）引起Smad信号通路的早期激活（Smad 2/3磷酸化、核转位和Smad依赖性基因转录）。通过针对活性TGF-β的中和抗体阻断TGF-β，不会改变Gremlin诱导的早期Smad活化。这些数据表明Gremlin通过TGF-β非依赖性过程直接激活Smad途径。在肾小管上皮细胞中，与Gremlin长期孵育增加了TGF-β的产生，并引起持续的Smad激活和表型转化为肌纤维母细胞样细胞。Smad 7过表达，这阻止了Smad 2/3的激活，减少了在Gremlin转染的肾小管上皮细胞中观察到的EMT变化。TGF-β中和也减少Gremlin诱导的EMT变化。结论：Gremlin可能通过激活Smad信号通路和诱导TGF-β诱导肾小管上皮细胞发生EMT，从而参与肾纤维化。
Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming growth factor-β (TGF-β). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial cells we have recently described that Gremlin induces EMT and acts as a downstream TGF-β mediator. Our aim was to investigate whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2) with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and Smad-dependent gene transcription). The blockade of TGF-β, by a neutralizing antibody against active TGF-β, did not modify Gremlin-induced early Smad activation. These data show that Gremlin directly, by a TGF-β independent process, activates the Smad pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF-β production and caused a sustained Smad activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation, diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF-β neutralization also diminished Gremlin-induced EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGF-β.
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影响因子：
82.9
作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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通讯作者：
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