Controlling the receptor for advanced glycation end-products to conquer diabetic vascular complications

Abstract

Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long-term diabetes. Extensive intracellular and extracellular formation of advanced glycation end-products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor-dependent mechanisms are involved in AGE-induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE-binding receptor, is now recognized as a member of pattern-recognition receptors and a pro-inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00191.x, 2012).

Keywords: Advanced glycation end‐products; Diabetic vascular complications; Receptor for advanced glycation end‐products.

Figure 1

Possible pathways of advanced glycation end‐products (AGE) formation. This is adapted from a review paper by Monnier et al.⁹⁵. The classical pathway leading to the formation of AGE involves Schiff base and Amadori products. The Amadori products can be transformed into reactive dicarbonyl products, such as glucosones, and can be fragmented by oxidation (glycoxidation) to generate pentosidine and N^ε‐carboxymethyl‐lysine (CML). Reactive dicarbonyls can also be generated from ketones, lipids, glycolysis and inflammatory pathways. Representative AGE are presented here. CEL, N^ε‐carboxyethyl‐lysine; 3‐DG‐imidazolone, 3‐deoxyglucosone‐imidazolone; GA‐pyridine, glycolaldehyde‐pyridine; GLAP, glyceraldehyde‐related pyridinium; GOLD, glyoxal‐derived lysine dimer; MG‐hydroimidazolone, methylglyoxal‐derived hydroimidazolone; MOLD, methylglyoxal‐derived lysine dimer.

Figure 2

Receptor for advanced glycation end‐products (RAGE) and its multiple ligands in the development of diabetic vascular complications. Soluble RAGE (sRAGE) and endogenous soluble RAGE (esRAGE) might work as decoy receptors against ligand‐receptor interactions. This is adapted from our review paper⁹⁶. AGE, advanced glycation end‐products; AOPP, advanced oxidation protein products; HMGB1, high‐mobility group box protein 1; NF‐κB, nuclear factor‐κB; PRR, pattern‐recognition receptors; TLR, toll‐like receptors.

Figure 3

Phenotypes of diabetic nephropathy in receptor for advanced glycation end‐products (RAGE) gene‐manipulated mice. KO, knockout mice; Tg, transgenic mice.

Figure 4

Splice variants of human and mouse receptor for advanced glycation end‐products (RAGE) genes. This is adapted from our original paper⁹⁷. esRAGE, endogenous secretory RAGE; ORF, open reading frame.