Pathogenesis of diabetic nephropathy, advanced glcation and new therapy

Abstract

It is well understood that persistent hyperglycemia contributes to diabetic tissue and end-organ damage [1], by promoting the formation of advanced glycosylation endproducts (AGEs) [2, 3]. AGEs form principally from the rearrangement of early glycation products, i.e. Amadori products, which produce a class o f stable moieties that possess distinctive chemical cross-linking and biological properties [2, 31 . It has been generally believed that proteins with half-lives of greater than a few weeks are most susceptible to advanced glycosylation and the highest levels o f AGEs occur on proteins that comprise the long-lived structural components of connective tissue matrix and basement membrane. Of particular interest, however, has been the recent observation that AGEs can also occur on short-lived proteins, on lipid constituents and on nucleic acids. This is most apparent under conditions o£ high AGE accumulation such as diabetes and renal failure, and results from the fact that AGE formation proceeds through a succession of reactive intermediates which can bind indiscriminantly to amino groups present on diverse "bystander" proteins. 1keactive intermediates can also be released from naturally degraded tissue AGE, only to bind again on other substances, if not cleared via the kidney, forming "second" generation AGEs. Cell surface receptors that are specific for the recognition, and degradation of AGE-modified proteins also have been identified on circulating monocytes, lymphocytes, endothelial, renal mesangial cells and other cellular systems to partake in both normal tissue remodeling and tissue damage. In this synoptic review, selected recent studies are highlighted which