Summary of Research Project Results under JSPS FY2001
"Research for the Future Program"



1.Research Institution Kanazawa University
 
2.Research Area Life Sciences
 
3.Research Field Genetic and Environmental Factors in Diseases Prevalent in Adults and the Elderly:Molecular and Cellular Mechanism of Vascular Complications
 
4.Term of Project FY 1997 〜 FY 2001
 
5.Project Number 97L00805
 
6.Title of Project Mechanisms for the Development of Diabetic Angiopathy and its Prevention

7.Project Leader
Name Institution,Department Title of Position
Hiroshi Yamamoto Kanazawa University, Graduate School of Medical Science Professor

8.Core Members

Names Institution,Department Title of Position
Toshio Doi Tokushima University, School of Medicine Professor
Hideto Yonekura Kanazawa University, Graduate School of Medical Science Associate Professor

9.Summary of Research Results

  This project has revealed both environmental and genic accounts for diabetic angiopathy, which has been sufferd from by a huge Japanese population. As the environmental account, various fractions of advanced glycation endproducts were found to cause vascular derangement characteristic of diabetes, e.g. pericyte loss and angiogenesis, and all of them were identified as ligands of RAGE, the cell surface receptor for AGE. Transgenic mice that overexpressed this receptor in their vasculature exhibited advanced diabetic vasculopathy, and this was prevented by an inhibitor of AGE formation. The mechanism of the regulation of human RAGE gene was also clarified; tumor necrosis factor-α, AGE ligands themselves and estradiol were identified as extracellular inducers, with an NF-ΚB site and a p65-p50 complex as the cis-element and trans-factor responsive to the former two inducers and with Sp-1 sites and an Sp-1 and estrogen receptor-α heteromer as the cis-element and trans-factor responsive to the latter. Novel RAGE splice variants were also discovered, among which a soluble form was found to be cytoprotective and to occur in human circulation. An ELISA screen of human diabetic patients revealed that serum levels of soluble RAGE are statistically significantly higher in those without vascular complications than in those with retinopathy or nephropathy. Factors that can influence the development of diabetic glomerulosclerosis were also identified; this included a novel transcription factor A1p145, collagen-specific molecular chaperon-HSP47, and Gas6.
  These molecular accounts this project has revealed are thus considered to be promising targets to overcome this life- and QOL-threatening disease.

10.Key Words

(1)Diabetic angiopathy、(2)AGE、(3)RAGE
(4)VEGF、(5)Soluble receptor、(6)Mesangial
(7)Collagen、(8)Chaperon、(9)Gas6


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