VEGF ameliorates tubulointerstitial fibrosis in unilateral ureteral obstruction mice via inhibition of epithelial-mesenchymal transition  

作　　者：Yao-guo LIAN Qiu-gen ZHOU Ying-juan ZHANG Fa-lei ZHENG 

机构地区：[1]Division of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China [2]Division of Nephrology, Southern Medical University Nanfang Hospital, Guangzhou 510515, China

出　　处：《Acta Pharmacologica Sinica》2011年第12期1513-1521,共9页中国药理学报（英文版）

基　　金：This project was supported by the National Natural Science Foundation of China （No 30570854）.

摘　　要：Aim： Vascular endothelial growth factor （VEGF） has been shown to be a survival factor for renal tubular epithelial cells. In the present study, we investigated whether administration of VEGF ameliorates tubulointerstitial fibrosis in a mouse model of unilateral ureteral obstruction （UUO）. Methods： Thirty-six male CD-1 mice were randomly divided into three groups： sham-operation, UUO and UUO＋VEGF group. VEGF （50 μg/kg） was subcutaneously injected twice daily from d 1 to d 14. Mice in each group were killed at d 3, 7, or 14 after the operation, and the tubulointerstitial fibrosis was histopathologically evaluated. Human proximal tubular epithelial cells （HK-2） were used for in vitro study. The expression levels of α-SMA, E-cadherin, TGF-β1, CTGF, and BMP-7 in the kidney were determined using Western blot and RT-PCR. Results： In the UUO mice, the degree of interstitial fibrosis was dramatically increased in a time-dependent manner. At d 3, 7, and 14, both the mRNA and protein expression levels for α-SMA, TGF-β1, and CTGF were significantly upregulated, whereas those for E-cadherin and BMP-7 were significantly downregulated. At d 3 and 7, VEGF treatment significantly reduced interstitial fibrosis and the expression levels for α-SMA, TGF-β1, and CTGF, while significantly increased the expression of E-cadherin and BMP-7, as compared with the UUO mice. At d 14 after operation, no significant differences were observed in the expression of the examined markers between VEGF- treated mice and UUO mice, with the exception of CTGF. In HK-2 cells, VEGF blocked TGF-β1-induced α-SMA and vimentin expression and restored E-cadherin expression in a dose-dependent manner. Conclusion： VEGF may ameliorate renal tubulointerstitial fibrosis at the early stage in UUO mice. This effect may be related to inhibition of VEGF on renal tubular epithelial-mesenchymal transition （EMT）.Aim： Vascular endothelial growth factor （VEGF） has been shown to be a survival factor for renal tubular epithelial cells. In the present study, we investigated whether administration of VEGF ameliorates tubulointerstitial fibrosis in a mouse model of unilateral ureteral obstruction （UUO）. Methods： Thirty-six male CD-1 mice were randomly divided into three groups： sham-operation, UUO and UUO＋VEGF group. VEGF （50 μg/kg） was subcutaneously injected twice daily from d 1 to d 14. Mice in each group were killed at d 3, 7, or 14 after the operation, and the tubulointerstitial fibrosis was histopathologically evaluated. Human proximal tubular epithelial cells （HK-2） were used for in vitro study. The expression levels of α-SMA, E-cadherin, TGF-β1, CTGF, and BMP-7 in the kidney were determined using Western blot and RT-PCR. Results： In the UUO mice, the degree of interstitial fibrosis was dramatically increased in a time-dependent manner. At d 3, 7, and 14, both the mRNA and protein expression levels for α-SMA, TGF-β1, and CTGF were significantly upregulated, whereas those for E-cadherin and BMP-7 were significantly downregulated. At d 3 and 7, VEGF treatment significantly reduced interstitial fibrosis and the expression levels for α-SMA, TGF-β1, and CTGF, while significantly increased the expression of E-cadherin and BMP-7, as compared with the UUO mice. At d 14 after operation, no significant differences were observed in the expression of the examined markers between VEGF- treated mice and UUO mice, with the exception of CTGF. In HK-2 cells, VEGF blocked TGF-β1-induced α-SMA and vimentin expression and restored E-cadherin expression in a dose-dependent manner. Conclusion： VEGF may ameliorate renal tubulointerstitial fibrosis at the early stage in UUO mice. This effect may be related to inhibition of VEGF on renal tubular epithelial-mesenchymal transition （EMT）.

关 键 词：VEGF unilateral ureteral obstruction renal tubulointerstitial fibrosis epithelial-mesenchymal transition transforming growth factor-β1 

分 类 号：Q78[生物学—分子生物学] Q51