Glycation and diabetes: The RAGE connection

The hyperglycaemic state seen in diabetes mellitus is associated with the development of diabetes-specific microvascular complications and accelerated macrovascular disease. Evidence implicates the formation and subsequent effects of advanced glycation endproducts (AGEs) as a contributing cause. AGEs exert their effects through interaction with the Receptor for AGE (RAGE) which upregulates expression of the receptor and induces a cascade of cytotoxic pathways. Accumulation of AGE/RAGE can be seen at sites of vascular disease in both animal models of diabetes and human diabetic subjects. Blockade of RAGE in animal models of diabetes suppresses development of dysfunction in the vasculature and atherosclerosis development. Genetic studies of RAGE reveal that a number of allelic variants of RAGE occur in key protein and regulatory domains. A Gly to Ser change at position 82 and two 5¢¢ flanking polymorphisms at position –374 and –429 lead to altered function and expression of RAGE which may impact on diabetic vascular disease development. Therapy aimed to block RAGE upregulation may prove to be useful in treating individuals with diabetic vascular disease

Diabetic vascular disease: it's all the RAGE

The major consequence of long-term diabetes is the increased incidence of disease of the vasculature. Of the underlying mechanisms leading to disease, the accumulation of advanced glycation end products (AGEs), resulting from the associated hyperglycemia, is the most convincing. Interaction of AGEs with their receptor, RAGE, activates numerous signaling pathways leading to activation of proinflammatory and procoagulatory genes. Studies in rodent models of macro- and microvascular disease have demonstrated that blockade of RAGE can prevent development of disease. These observations highlight RAGE as a therapeutic target for treatment of diabetic vascular disease

Blockade of receptor for advanced glycation endproducts: a new target for therapeutic intervention in diabetic complications and inflammatory disorders

The glycation and oxidation of proteins/lipids leads to the generation of a new class of biologically active moieties, the advanced glycation endproducts (AGEs). Recent studies have elucidated that carboxymethyllysine (CML) adducts of proteins/lipids are a highly prevalent AGE in vivo. CML-modified adducts are signal transduction ligands of the receptor for AGE (RAGE), a member of the immunoglobulin superfamily. Importantly, CML-modified adducts accumulate in diverse settings. In addition to enhanced formation in settings of high glucose, these adducts form in inflammatory milieu. Studies performed both in vitro and in vivo have suggested that the proinflammatory/tissue destructive consequences of RAGE activation in the diabetic/inflamed environment may be markedly attenuated by blockade of the ligand–RAGE axis. Here, we will summarize the known consequences of RAGE activation in the tissues and highlight novel areas for therapeutic intervention in these disease states

Posttranslationally Modified Proteins as Mediators of Sustained Intestinal Inflammation

Oxidative and carbonyl stress leads to generation of N(ε)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-κB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-κB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-κB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-κB activation in cultured endothelial cells, which was mediated by CML-mps including CML-modified S100 proteins. The resulting NF-κB activation, lasting 5 days, was primarily inhibited by either depletion of CML-mps or by the addition of sRAGE, p44/42 and p38 MAPKinase-specific inhibitors. Consistently, CML-mps isolated from inflamed gut areas and rectally applied into mice caused NF-κB activation, increased proinflammatory gene expression, and histologically detectable inflammation in wild-type mice, but not in RAGE(−/−) mice. A comparable up-regulation of NF-κB and inflammation on rectal application of CML-mps was observed in IL-10(−/−) mice. Thus, CML-mps generated in inflammatory lesions have the capacity to elicit a RAGE-dependent intestinal inflammatory response