Heparanase induced by advanced glycation end products (AGEs) promotes macrophage migration involving RAGE and PI3K/AKT pathway

Cardiovascular Diabetology

Original Investigation

Jianying Niu¹  Qiaojing Qin¹  Yong Gu²  Wangjie Xu³  Zhongdong Qiao³  Zhaoxia Wang³ 

[1] Department of Nephrology, Shanghai Fifth People’s Hospital, Fudan University, 200240, Shanghai, China;Department of Nephrology, Shanghai Fifth People’s Hospital, Fudan University, 200240, Shanghai, China;Department of Nephrology, Huashan Hospital, Fudan University, 200240, Shanghai, China;School of Life Science and Biotechnology, Shanghai Jiaotong University, 200240, Shanghai, China;

关键词: Advanced glycation end products;    Macrophage migration;    Diabetes;    RAGE;    Heparanase;    PI3K/AKT;   

DOI  :  10.1186/1475-2840-12-37

 received in 2013-01-15, accepted in 2013-02-18,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundAdvanced glycation end products (AGEs), inflammatory-associated macrophage migration and accumulation are crucial for initiation and progression of diabetic vascular complication. Enzymatic activity of heparanase (HPA) is implicated strongly in dissemination of metastatic tumor cells and cells of the immune system. In addition, HPA enhances the phosphorylation of selected signaling molecules including AKT pathway independent of enzymatic activity. However, virtually nothing is presently known the role of HPA during macrophage migration exposed to AGEs involving signal pathway.MethodsThese studies were carried out in Ana-1 macrophages. Macrophage viability was measured by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays. HPA and AKT protein expression in macrophages are analysed by Western blotting and HPA mRNA expression by real time quantitative RT-PCR. Release of HPA was determined by ELISA. Macrophage migration was assessed by Transwell assays.ResultsHPA protein and mRNA were found to be increased significantly in AGEs-treated macrophages. Pretreatment with anti-HPA antibody which recognizes the nonenzymatic terminal of HPA prevented AGEs-induced AKT phosphorylation and macrophage migration. LY294002 (PI3k/AKT inhibitor) inhibited AGEs-induced macrophage migration. Furthermore, pretreatment with anti-receptor for advanced glycation end products (RAGE) antibody attenuated AGEs-induced HPA expression, AKT phosphorylation and macrophage migration.ConclusionsThese data indicate that AGEs-induced macrophage migration is dependent on HPA involving RAGE-HPA-PI3K/AKT pathway. The nonenzymatic activity of HPA may play a key role in AGEs-induced macrophage migration associated with inflammation in diabetic vascular complication.

【 授权许可】

Unknown   
© Qin et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.