Regulation of angiogenin expression and epithelial-mesenchymal transition by HIF-1α signaling in hypoxic retinal pigment epithelial cells.
Choroidal neovascularization (CNV) is a major cause of vision loss in many retinal diseases. Hypoxia is determined to be a key inducer of CNV and hypoxia-inducible factor-1 (HIF-1) is an important transcription factor. Epithelial-mesenchymal transition (EMT) and the synthesis of proangiogenic cytokines make great contributions to the development of CNV. In the present study, the role of HIF-1α signaling in the regulation of angiogenin (ANG) expression and EMT in hypoxic retinal pigment epithelial cells was investigated. A significant elevation expression of ANG expression level in a mouse model of laser-induced CNV was demonstrated. In a hypoxic model of ARPE-19, an increased expression level of ANG and induction of EMT accompanied with stabilization and nucleus translocation of HIF-1α. Blockage of HIF-1α signaling resulted in inhibition of high expression of ANG and EMT features. The direct interaction between HIF-1α and ANG promoter region was identified by ChIP-qPCR. The association of RNase 4 mRNA level with HIF-1α signaling was also clarified in APRE-19. Moreover, the exogenous ANG translocated into the nucleus, enhanced 45S rRNA transcription, promoted cell proliferation and tube formation in human retinal microvascular endothelial cells. In conclusion, the hypoxic conditions regulate the expression of ANG and EMT via an activation of HIF-1α signaling. It provides molecular evidence for potential therapy strategies of treating CNV.
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Hangzhou, China.
Kairan
K
Lai
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Hangzhou, China.
Chenqi
C
Luo
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xiaobo
X
Zhang
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Panpan
P
Ye
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Yidong
Y
Zhang
Institutes of Environmental Medicine, School of Medicine, Zhejiang University, Hangzhou, China.
Jiliang
J
He
Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Hangzhou, China. Electronic address: xlren@zju.edu.cn.
Ke
K
Yao
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology*; D012259:Ribonuclease, Pancreatic / Q000235:genetics*; D015398:Signal Transduction; D015854:Up-Regulation
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C046366:angiogenin; D012259:Ribonuclease, Pancreatic
Angiogenin; Choroidal neovascularization; Epithelial-mesenchymal transition; Hypoxia-inducible factor-1; RNase 4