MicroRNA-dependent cross-talk between VEGF and HIF1¦Á in the diabetic retina
详细信息 查看全文
- 作者：Shukuan Ling ; Yochai Birnbaum ; Manjyot K Nanhwan ; Bejoy Thomas ; M ; eep Bajaj ; Yumei Ye
- 关键词：CeRNA ; competing endogenous RNA ; DKK1 ; Dickkopf-1 ; DM ; diabetes mellitus ; DR ; diabetic retinopathy ; HG ; high glucose ; HIF1¦Á ; hypoxia-inducible factor 1-alpha ; ICAM-1 ; intercellular adhesion molecule-1 ; miRNA ; microRNA ; MRE ; microRNA response element ; mRN
- 刊名：Cellular Signalling
- 出版年：2013
- 出版时间：December, 2013
- 年：2013
- 卷：25
- 期：12
- 页码：2840-2847
- 全文大小：1306 K
文摘
Both HIF1¦Á (hypoxia-inducible factor alpha) and VEGF (vascular endothelial growth factor) are implicated in the pathogenesis of diabetic retinopathy (DR). Competitive endogenous RNAs (ceRNAs) are messenger RNA (mRNA) molecules that affect each other expression through competition for their shared microRNAs (miRNA). However, little is known about the role of ceRNAs in DR. We assess whether the expression of HIF1¦Á and VEGF in DR is interdependent through sequestration of common miRNAs. We used bioinformatics to identify potential miRNAs that affect both genes and validated the interdependence of the genes by silencing or overexpression of the genes and assessed the luciferase-HIF1¦Á 3¡äUTR activity. We found that HIF1¦Á and VEGF are targeted by 12 common miRNAs. Silencing either HIF1¦Á or VEGF increased the availabilities of the shared miRNAs, therefore suppressed the luciferase-HIF1¦Á 3¡äUTR activity, whereas over-expressing HIF1¦Á or VEGF increased the luciferase activity. HIF1¦Á was co-expressed with VEGF in-vivo and in-vitro in DR models. Silencing HIF1¦Á transcripts resulted in a significant reduction in VEGF protein levels and vice versa. This interdependence was miRNA- and 3¡äUTR-dependent, as silencing Dicer abolished the interdependence. Over-expression of a common miRNA (miR-106a) significantly reduced the expression of HIF1¦Á and VEGF and prevented high glucose-induced increased permeability. There is a cross-talk between HIF1¦Á and VEGF through interactions with their common miRNAs. miRNA based therapy can affect the expression of both HIF1¦Á and VEGF and may represent a therapeutic potential for the treatment of DR.