Kinetics, role and therapeutic implications of endogenous soluble form of receptor for advanced glycation end products (sRAGE) in diabetes

Sho-ichi Yamagishi, Takanori Matsui, Kazuo Nakamura
Current Drug Targets 2007, 8 (10): 1138-43
Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products. These early glycation products undergo further complex reaction such as rearrangement, dehydration, and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs have been known to progress at an accelerated rate in diabetes. There is a growing body of evidence that AGEs and their receptor (RAGE) axis is implicated in the pathogenesis of diabetic vascular complications. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. Moreover, administration of a recombinant soluble form of RAGE (sRAGE), has been shown to suppress the development of accelerated atherosclerosis in diabetic apolipoprotein E-null mice. These observations suggest that exogenously administered sRAGE may capture and eliminate circulating AGEs, thus protecting against the AGEs-elicited tissue damage by acting as a decoy receptor. Recently, endogenous sRAGE has been identified in humans. However, there is few comprehensive review about the regulation and role of endogenous sRAGE in diabetes. In the former part of this paper, we review the role of the AGE-RAGE system in the pathogenesis of diabetic vascular complications. Then we summarize in the latter part of this review the kinetics and pathophysiological role of endogenous sRAGE in diabetes. We also discuss the possibility that endogenous sRAGE may be a therapeutic target for the prevention of diabetic vascular complications.

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