Study on file RAGE signaling in vascular cells - a novel mechanism of the development of diabetic vascular complications

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In this research, we provide the first direct in vivo evidence that interactions between advanced glycation end products (AGE) and their receptor, RAGE, lead to diabetic vascular derangements. We also found the presence of a cytoprotective secretory form of RAGE (endogenous secretory RAGE, esRAGE) in human and identified new RAGE ligands, which are abundantly present in human circulation.(1) We created transgenic mice that overexpress human RAGE in vascular cells. The diabetic RAGE transgenic mice exhibited an accelerated development of diabetic nephropathy. This transgenic mouse will be a useful animal model that shows the renal changes seen in humans.(2) We also created transgenic mice that overexpress human RAGE in the heart and obtained evidence suggesting that the AGE and RAGE could play an active role in the development of diabetes-induced cardiac dysfunction.(3) We created RAGE gene-knockout mice and showed that the advanced diabetic nephropathy was significantly suppressed in the diabetic knockout mice.(4) We demonstrated that human vascular endothelial cells (EC) and pericytes express a novel splice variant encoding a novel secretory form of RAGE (esRAGE). The AGE induction of ERK phosphorylation and vascular endothelial growth factor in EC and of the growth and cord-like structure formation of EC was perfectly abolished by this RAGE variant, indicating that esRAGE is cytoprotective against AGE. The findings may contribute to our understanding of the molecular basis for the diversity of cellular responses to AGE and for individual variations in susceptibility or resistance to diabetic vascular complications.(5) We identified glyceraldehyde- and glycolaldehydee-derived AGE as new RAGE ligands. The AGE fractions increased VEGF mRNA levels in human EC as well as cell growth. These results suggested that glyceraldehyde- and glycolaldehyde-derived AGE participate in vascular injury in diabetes.