Epithelial-to-mesenchymal transition and slit function of mesothelial cells are regulated by the cross talk between mesothelial cells and endothelial cells
Epithelial-to-mesenchymal transition and slit function of mesothelial cells are regulated by the cross talk between mesothelial cells and endothelial cells
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DOI：
10.1152/ajprenal.00543.2013
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
Toda, Shuji
中科院分区：
文献类型：
--
作者：
Aoki, Shigehisa;Takezawa, Toshiaki;Toda, Shuji
腹膜功能障碍是导致腹膜透析治疗失败的主要因素。然而，与帕金森病相关的腹膜扩散改变的确切机制仍有待阐明。为此，我们建立了一种新型的体外腹膜扩散模型，该模型由胶原玻璃体膜室三维培养系统和流体流产生系统组成。这一人造腹膜模型显示，高糖培养液和流体压力促进了间皮细胞的上皮-间充质转化(EMT)过程，而内皮细胞抑制了这一间皮EMT过程。EMT状态的间皮细胞结缔组织生长因子高表达，骨形态发生蛋白-7低表达，而非EMT状态的间皮细胞这两种蛋白的表达模式相反。此外，这些蛋白的表达依赖于模型中内皮细胞的存在。我们的模型表明，内皮细胞的缝隙功能主要依赖于覆盖表面，而间皮层对小分子溶质具有独立于表面的特定屏障功能。值得注意的是，低糖预处理存在间皮细胞和内皮细胞的协同屏障效应，但高糖预处理取消了这种协同效应。这些发现表明间皮缝隙功能不仅受高糖诱导的EMT过程的调节，而且还受内皮旁分泌效应的影响。该腹膜扩散模型有望成为帕金森病发展的一种新工具。
Peritoneal dysfunction is a major factor leading to treatment failure of peritoneal dialysis (PD). However, the precise mechanism of the peritoneal diffusion changes related to PD remains to be elucidated. To this end, we have established a novel peritoneal diffusion model in vitro, which consists of a three-dimensional culture system using a collagen vitrigel membrane chamber and a fluid-stream generation system. This artificial peritoneal model revealed that high-glucose culture medium and fluid flow stress promoted the epithelial-mesenchymal transition (EMT) process of mesothelial cells and that endothelial cells inhibited this mesothelial EMT process. Mesothelial cells in the EMT state showed high expression of connective tissue growth factor and low expression of bone morphogenic protein-7, while non-EMT mesothelial cells showed the opposite expression pattern of these two proteins. In addition, these protein expressions were dependent on the presence of endothelial cells in the model. Our model revealed that the endothelial slit function was predominantly dependent on the covering surface area, while the mesothelial layer possessed a specific barrier function for small solutes independently of the surface area. Notably, a synergic barrier effect of mesothelial cells and endothelial cells was present with low-glucose pretreatment, but high-glucose pretreatment abolished this synergic effect. These findings suggest that the mesothelial slit function is not only regulated by the high-glucose-induced EMT process but is also affected by an endothelial paracrine effect. This peritoneal diffusion model could be a promising tool for the development of PD.