Adenovirus-mediated anti-sense ERK2 gene therapy inhibits tubular epithelial–mesenchymal transition and ameliorates renal allograft fibrosis

详细信息    查看全文

• 作者：Zhao Ding^a ; ^b ; ¹ ; Zhishui Chen^a ; ¹ ; Xilin Chen^a ; Ming Cai^a ; Hui Guo^a ; Xiaoping Chen^a ; Nianqiao Gong^a ; ^{nqgong@tjh.tjmu.edu.cn"" rel=""nofollow}
• 关键词：Renal allograft fibrosis ; Epithelial– ; mesenchymal transition (EMT) ; Extracellular signal-regulated kinase (ERK) ; Adenovirus-mediated anti-sense ERK2 (Adanti-ERK2) gene therapy ; Renal transplantation
• 刊名：Transplant Immunology
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：25
• 期：1
• 页码：34-41
• 全文大小：1700 K

文摘

Purpose

Epithelial–mesenchymal transition (EMT) plays an important role in progress of renal allograft fibrosis. The adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 (Adanti-ERK2) gene therapy was used to block ERK signaling pathway, and its effect on EMT and renal allograft fibrosis both in vivo and in vitro was explored.

Methods

We first generated an in vitro EMT model by connective tissue growth factor (CTGF) stimulation in a HK-2 cell culture system, and then applied Adanti-ERK2 gene therapy on it. The transition of epithelial marker (E-cadherin) to mesenchymal markers (α-SMA, Vimentin) and the cell mobility function alteration were monitored for the observation of EMT progress. In vivo, a rat renal transplant model with Fisher–Lewis combination was employed and the Adanti-ERK2 gene therapy was given. The tubular EMT changes and pathology of allograft fibrosis were examined.

Results

In vitro, Adanti-ERK2 gene therapy inhibited CTGF-induced tubular EMT and attenuated the cell motility function induced by CTGF. In vivo, Adanti-ERK2 gene therapy attenuated tubular EMT, modulated the infiltration of macrophages and CD8⁺, CD4⁺T lymphocytes, and ameliorated fibrosis effectively in the renal allografts 24 weeks after transplantation.

Conclusions

Adanti-ERK2 gene therapy inhibits tubular EMT and attenuates renal allograft fibrosis. It is possible to develop promising molecular drug(s) in the future based on ERK signaling pathway.