2007 Fiscal Year Final Research Report Summary
Soluble Receptor for AGEs in diabetes, platelet activation and atherosclerosis
| Project/Area Number |
17590946
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Metabolomics
|
|---|
| Research Institution | Osaka City University |
|---|
Principal Investigator |
KOYAMA Hidenori Osaka City University, Medicine, Lecturer (80301852)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Hiroshi Kanazawa University, Medicine, Professor (00115198)
|
|---|
| Project Period (FY) |
2005 – 2007
|
| Keywords | atherosclerosis / metabolic syndrome / diabetes / aneioeenesis |
|---|
| Research Abstract |
Receptor for AGEs (RAGE) is involved in macro- and microvascular complications in diabetes. RAGE is a cell surface receptor belongs to the immunoglobulin superfamily. Ligation of AGEs with RAGE results in activation of cellular signaling pathway including NF-KB activation. Analyses of the phenotypes of RAGE-overexpressing and -knockout mice revealed that RAGE is deeply involved in progression of diabetic nephropathy. Moreover, RAGE expression is upregulated in atherosclerotic plaques of diabetic animals, and augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE. We have also shown that RAGE is involved in diabetes impairment of angiogenic response, which is implicated in acceleration of severity following ischemia. An endogenous secretory RAGE (esRAGE) has been identified as a novel splice variant carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains. esRAGE is released outside from the cells, and is detected in human plasma. Plasma esRAGE is significantly lower in patients with diabetes and hypertension. Of note, plasma esRAGE is significantly and inversely correlated with components of the metabolic syndrome including body mass index, triglyceride, or an insulin resistance index. In a cohort of end-stage renal diseases (ESRD), cumulative incidence of cardiovascular death is significantly higher in subjects in the lowest tertile of plasma esRAGE, independent of the presence of diabetes. Moreover, adenoviral overexpression of esRAGE in mice significantly recovered vascular dysfunction in diabetes. Thus, we postulate that plasma esRAGE is a potential protective factor and a novel biomarker against atherosclerosis and metabolic syndrome.
|
