Nurture vs. nature in diabetic vasculopathy: roles of advanced glycation endproducts and the receptor for them

Abstract

As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies conducted in this lab revealed advanced glycation endproducts (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes, and the receptor for AGE (RAGE) as the major genetic factor that responds to them. AGE fractions that caused the vascular derangement were proven to be RAGE ligands. When made diabetic, RAGE-overexpressing transgenic mice exhibited the exacerbation of the indices of nephropathy, and this was prevented by the inhibition of AGE formation. We also created RAGE-deficient mice. They showed marked amelioration of diabetic nephropathy. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A) + RNA, we came across a novel splice variant coding for a soluble RAGE protein, and named it endogenous secretory RAGE (esRAGE). esRAGE was able to capture AGE ligands and neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE–RAGE system should thus be regarded as a candidate molecular target for overcoming this life- and quality of life (QOL)-threatening disease.