Transforming Growth Factor-β1 Induces Endothelial-to-Mesenchymal Transition via Akt Signaling Pathway in Renal Transplant Recipients with Chronic Allograft Dysfunction
Zijie Wang, Zhijian Han, Jun Tao, Jun Wang, Xuzhong Liu, Wanli Zhou, Zhen Xu, Chunchun Zhao, Xiaobin Ju, Zengjun Wang, Ruoyun Tan, Min Gu
(Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China (mainland))
Ann Transplant 2016; 21:775-783
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.
Keywords: Kidney Transplantation, Transendothelial and Transepithelial Migration, Transforming Growth Factor beta1