Mechanisms of vascular injury in diabetes: lessons from vascular cells in culture and transgenic animals
Hiroshi Yamamoto (Japan)
Microvessels are composed of two cell types, endothelial cells (EC) and pericytes. The decrease in the latter (pericyte loss) and the increase in the former (angiogenesis) are the hallmarks of diabetic retinopathy. Coculture experiments revealed that the growth and function of EC are under a control of neighboring pericytes, thus explaining why endothelial derangement follows pericyte loss. During prolonged hyperglycemic exposure, nonenzymatically glycated protein derivatives termed advanced glycation endoproducts (AGE) are formed at an accelerated rate and accumulate in palsma and various tissues. When bovine retinal pericytes were cultured with AGE-bovine serum albumin, the number of viable pericytes was decreased, which was abolished by a DNA complement of mRNA coding for a cell-surface receptor for AGE (RAGE). AGE can act also on EC, again in a RAGE-dependent manner. They stimulated the proliferation and tube formation of microvascular EC, and inhibited prostacyclin synthesis but induced plasminogen activator inhibitor-1. Thus, AGE predispose to both angiogenesis and thrombogenesis. The angiogenic activity of AGE was found to be mediated by autocrine vascular endothelial growth factor. To address the role of RAGE in the development of diabetic pathology, we created transgenic mice that overexpress RAGE in vascular cells and made them diabetic by crossbreeding with another transgenic line that develops insulin-dependent diabetes early after birth. The resultant double transgenic mice exhibited accelerated nephropathy as evidenced by significantly higher scores in albuminuria, glomerulosclerosis and serum creatinine compared with single transgenic and nontransgenic littermates. The nephropathy was ameliorated by the administration of an inhibitor of AGE formation. Indices diagnostic of diabetic retinopathy were also prominent in the double transgenic mouse model. Further, the regulators of RAGE gene expression have been identified. Transcription of human RAGE gene was induced by tumor necrosis factor- a and AGE ligands themselves through nuclear factor- K B activation, and by 17 /3 -estradiol through Sp-1. The results thus suggest that the AGE-RAGE system plays an active role in the development of diabetic vasculopathy and is a promising target in the prophylaxis and therapy of this disease.
Biomed Rev 2000; 11:19-27.
Received 12 September 2000 and accepted 2 November 2000.
Correspondence and reprint requests to Dr Hiroshi Yamamoto, Department of Biochemistry, School of Medicine, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan. Tel.: 81 76 265 2180, Fax: 81 76 234 4226,