title: O-GlcNAc modification of Sp1 mediates hyperglycaemia-induced ICAM-1 up-regulation in endothelial cells.
abstract: Intracellular adhesion molecule 1 (ICAM-1) is an important inflammatory factor that causes retinal damage during diabetic retinopathy. Hyperglycaemia can increase ICAM-1 expression in endothelial cells and the ICAM-1 promoter is responsive to the transcription factor specificity protein 1 (Sp1). O-GlcNAc modification is driven by the glucose concentration and has a profound effect on Sp1 activity. In this study, we investigated the underlying mechanism through which hyperglycaemia triggers ICAM-1 expression, which is mediated by O-GlcNAc modification of Sp1 in human umbilical vein endothelial cells (HUVECs) and rat retinal capillary endothelial cells (RRCECs). We showed that hyperglycaemia (30 mM) increased ICAM-1 expression compared to control conditions (5 mM). The addition of an OGT inhibitor decreased ICAM-1 expression and addition of an OGA inhibitor enhanced ICAM-1 expression. Furthermore, cells transduced with siSp1 exhibited dramatically decreased ICAM-1 expression. These results proved that the up-regulation of ICAM-1 with hyperglycaemia is mediated by O-GlcNAc modification of Sp1. It helps to explain the mechanism of ICAM-1 processing in HUVECs and RRCECs. Understanding how this inflammatory factor is modulated during diabetic retinopathy will ultimately help to design novel therapeutics to treat this condition.
authors.affiliation: Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Niu
authors.affiliation: Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China. Electronic address: drliukun@sjtu.edu.cn.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D000215:Acylation; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016329:Sp1 Transcription Factor; D018799:Intercellular Adhesion Molecule-1; D000117:Acetylglucosamine
keywords: Hyperglycaemia; ICAM-1; O-GlcNAc; Sp1