Transforming Growth Factor-β1 Induces Endothelial-to-Mesenchymal Transition via Akt Signaling Pathway in Renal Transplant Recipients with Chronic Allograft Dysfunction
Transforming Growth Factor-β1 Induces Endothelial-to-Mesenchymal Transition via Akt Signaling Pathway in Renal Transplant Recipients with Chronic Allograft Dysfunction
复制标题
转化生长因子-β1 通过 Akt 信号通路在患有慢性同种异体移植功能障碍的肾移植受者中诱导内皮细胞向间质细胞的转变。
DOI：
10.12659/aot.899931
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发表时间：
2016-12-20
影响因子：
1.1
通讯作者：
Gu, Min
中科院分区：
文献类型：
--
作者：
Wang, Zijie;Han, Zhijian;Gu, Min
慢性移植物功能障碍（CAD）是肾移植受者移植物慢性失功的主要原因。肾间质纤维化被认为与肾移植中的CAD密切相关。近年来，内皮细胞向间质细胞转化（EndMT）被认为是肾间质纤维化的潜在机制之一。材料与方法收集25例肾移植受者（RTR）和健康志愿者的肾组织标本，分别进行HE、Masson三色染色、免疫组化染色和间接免疫荧光双染色。此外，培养人脐静脉内皮细胞（HUVECs），并以不同剂量或时间间隔给予TGF-β1处理。Western blot检测α-SMA和CD 31蛋白表达。此外，还通过Western blotting方法研究了TGF-β 1诱导EndMT的可能信号通路。结果CAD组移植肾组织可见典型的间质纤维化。TGF-β1在肾组织中的表达也明显高于正常肾组织。CAD组肾组织中α-SMA、I型胶原和III型胶原表达明显增强，而CD 31表达减弱。TGF-β1处理HUVECs后，α-SMA和CD 31蛋白表达呈时间和剂量依赖性。TGF-β1和选择性抑制剂可诱导HUVECs激活Akt信号通路。结论CAD大鼠肾组织中存在EndMT，TGF-β1可通过Akt信号通路以时间和剂量依赖的方式诱导EndMT的形成。
BACKGROUND Chronic allograft dysfunction (CAD) is the major cause of chronic loss of allograft in kidney transplant recipients. Kidney interstitial fibrosis is identified to be strongly associated with CAD in kidney transplantation. Recently, endothelial-to-mesenchymal transition (EndMT) has been identified as one of the potential mechanisms in kidney interstitial fibrosis. MATERIAL AND METHODS Kidney tissue samples from 25 renal transplant recipients (RTRs) with CAD and healthy volunteers were collected for HE (hematoxylin-eosin), Masson trichrome, and immunohistochemical staining, and indirect immunofluorescence double-staining assay. Moreover, human umbilical vascular endothelial cells (HUVECs) were cultured and treated with TGF-β1 at different doses or intervals. The protein expressions of α-SMA and CD31 were determined by Western blot assay. Furthermore, potential signaling pathways involved in EndMT induced by TGF-β1were also investigated by Western blotting. RESULTS Typical interstitial fibrosis was observed in transplanted renal tissues from the CAD group. We also found a significant increase of TGF-β1 expression in renal tissues from RTRs with CAD compared with the normal group. Moreover, significant over-expressions of α-SMA, collagen-I, and collagen-III and under-expression of CD31 were detected in kidney specimens of the CAD group. Similar expressive tendencies of α-SMA and CD31 proteins were found in HUVECs treated with TGF-β1 in both time-dependent and dose-dependent manners. The activation of the Akt signaling pathway was found in HUVECs induced by TGF-β1 and selective inhibitors. CONCLUSIONS EndMT was observed in kidney tissues from RTRs with CAD, and TGF-β1 can induce the process of EndMT in both time-dependent and does-dependent manners through the Akt signaling pathway.