TAKEUCHI Masayoshi Kanazawa University, Department of Parmacology, Instructor, 薬学部, 講師 (20154982)
YAMAMOTO Yasuhiko Kanazawa University, Graduate School of Medical Science, Instructor, 医学系研究科, 助手 (20313637)
YONEKURA Hideto Kanazawa University, Graduate School of Medical Science, Associated Professor, 医学系研究科, 助教授 (80240373)
In this research, we revealed that the novel species of advance glycation endproducts (AGE), whose level in serum is elevated in diabetic patients, do bind to their cellular receptor RAGE and induce intracellular signals.We also identified a novel splicing variant of RAGE-endogenous secretory RAGE (esRAGE)-and found that this variant has protective effect against vascular injury induced by the novel AGE species. Moreover, we found the significant coirelation between serwn esRAGE level and susceptibility of some life-style related diseases.
(1) We demonstrated that the novel AGE species, which is generated by incubating bovine serum albumin with glyceraldehyde or glycolaldehyde, strongly binds to cellular RAGE at comparable dissociation constants calculated by the suiface plasmon resonance method.
(2) We mapped the binding region of the novel AGEs on RAGE at an inununoglobulin V-domain-like region on its N-terminal end.
(3) We demonstrated that the interaction of the new AGEs to RAGE activated MAP kinase signaling pathway and induced V CAM-i expression in cultured human endothelialcells.
(4) We created RAGE knockout mice and demonstrated that the development of diabetic nephropa thy was dramatically suppressed in the absence of RAGE..
(5) We isolated a novel splicing variant of RAGE from human endothelial cells that lacks transmembrane domain and is secreted from cells, and termed this novel variant esRAGE (~ndogenous secretory RAGE).
(6) Furthennore we found that esRAGE has a protective effect against the vascular injuly induced by the novel AGEs, by extracellular capture of the RAGE lingads.
(7) We established esRAGE ELISA system and analyzed serum level of esRAGE in patients with life-style related deseases. Then we found significant correlation between serum esRAGE level and susceptibility of some life-style related diseases, suggesting that. the serum esRAGE level could be a useful risk marker for some life-style related deseases.