Identification of a novel AGE-capturable soluble variant of the RAGE in human sera

Abstract Engagement by advanced glycation endproducts (AGE) of the cell surface receptor for AGE (RAGE) leads to perturbation of vascular cell functions. This includes proliferation of endothelial cells (EC), and decrease in pericytes. To clarify these different cellular responses, we analyzed in this study polysomal mRNAs for RAGE from human microvascular EC and pericytes by RT-PCR cloning, and isolated three major variants: novel C-terminally and N-terminally truncated forms and the known full-length form. The protein product of the C-terminally truncated variant was secreted into culture media, whereas the N-terminally truncated form resided on the plasma membrane, when each cDNA was forced to be expressed in COS-7 cells. The former, soluble form of RAGE was actually detected in healthy human sera, and was found capable of neutralizing AGE induction of vascular endothelial growth factor (VEGF) gene in EC. Different degrees of the expression of those RAGE variants may elicit different cellular responses to AGE, and such variation may contribute to the individual susceptibility or resistance to the development of diabetic complications.