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

• Published in: Acta pharmacologica Sinica 2011-12, Vol.32 (12), p.1513-1521
• Main Authors: Lian, Yao-guo, Zhou, Qiu-gen, Zhang, Ying-juan, Zheng, Fa-lei
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Epithelial-Mesenchymal Transition; Fibrosis - prevention & control; Humans; Immunology; Internal Medicine; Male; Medical Microbiology; Mice; Original; original-article; Pharmacology/Toxicology; Ureteral Obstruction - pathology; Vaccine; Vascular Endothelial Growth Factor A - physiology; 单侧; 小鼠; 梗阻; 纤维化; 肾小管上皮细胞; 血管内皮生长因子; 输尿管; 间质
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2011.111

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）.