Abstract :
Proteins or lipids exposed to reducing sugars undergo nonenzymatic glycation and oxidation. Initially, reversible early glycation adducts form, the best-known of which is hemoglobin A1c. Following complex molecular rearrangements, the irreversible advanced glycation endproducts (AGEs) develop. These constitute a heterogeneous class of structures of yellow-brown color, with a propensity to form crosslinks, that generate reactive oxygen intermediates and interact with particular cell surface structures. AGEs accumulate in the plasma and vessel wall during normal aging, and to accelerated degree in diabetic subjects. AGEs are important because they are believed to contribute to the pathogenesis of diabetic complications. One of the principal means by which AGEs perturb cellular functions is by interaction with these cellular surface structures, the best-characterized of which is Receptor for AGEs or RAGE, a member of the immunoglobulin superfamily of cell surface molecules. RAGE is present in a variety of cell types involved in diabetic complications, such as the vasculature (endothelial cells and vascular smooth muscle cells), mononuclear phagocytes, mesangial cells and certain neurons. RAGE mediates monocyte migration and activation in response to AGEs, although other binding sites may also contribute. Engagement by AGE of endothelial RAGE induces cellular oxidant stress, thereby increasing vascular permeability and activating the transcription factor NF-kB; consequences of the latter event include enhanced cell surface expression of vascular cell adhesion molecule-1 (VCAM-1), and increased expression of Interleukin-6 by macrophages. We have found that the extracellular domain of RAGE (soluble or sRAGE) binds avidly to AGEs and appears to render them biologically inert with respect to interaction with such target cells. These considerations form the basis of present studies aimed at mitigating the consequences of AGE-RAGE interaction with respect to the pathogenesis of diabetic complications.
