**3. RAGE**

AGEs could exert their actions not only directly but also through a receptor system, which includes two types of cell surface AGEs receptors: first type is that binds AGEs and initiates cell activation and second type is that binds and degrades AGEs. Receptor for AGEs (RAGE) is one receptor of the first type; it recognizes AGEs and initiates oxidative stress. The second type of receptors consists of AGER1, AGER3, and CD36 [26, 27]. However, it is noteworthy that there are other AGE receptors, such as the macrophage scavenger receptor and the galectin-3 receptor, which might have similar deleterious effects to RAGE when they interact with AGEs [28].

RAGE is a multi-ligand receptor of the immunoglobulin superfamily of cell surface molecules acting as a receptor not only for several molecules including AGEs but also for S100/calgranulins and amyloid. Circulating isoforms of RAGE include soluble RAGE (sRAGE) that has been cleaved from the cell surface by matrix metalloproteinases and endogenous secretory RAGE (esRAGE), and a splice variant of RAGE that is secreted into blood. Both sRAGE and esRAGE protect body against the AGEs-elicited tissue damage by acting as a decoy receptor for AGEs [29, 30]. The ligands of RAGE have a common feature that they accumulate in tissues during aging, inflammation, and degenerative diseases. Engagement of RAGE results in intracellular signaling that leads to the activation of NF-kB, a pro-inflammatory transcription factor, which is then translocated to the nucleus and subsequently activates the transcription of target genes [31]. These include genes of cytokines, adhesion molecules, and prothrombotic and vasoconstrictive products. The activation of NF-kB results in upregulation of the receptors in return. In addition, cellular-signaling cascades such as the ERK signaling pathway and PI-3 kinases are activated by the binding of ligands with RAGE [32].

In the skin, RAGE expression was observed in both epidermis and dermis, and it was increased in sun-exposed compared with UV irradiation-protected areas [33]. Not only in vivo, but also in vitro, various skin cells types have been shown to express RAGE [34–36], such as keratinocytes, fibroblasts, dendritic cells, and to a lesser extent endothelial cells and lymphocytes. Patients with diabetes also exhibit increased immunoreactivity for RAGE and AGEs. For example, in sural nerve biopsies, AGE-RAGE interaction was found which suggests it may have a clinical role in neuronal dysfunction that leads to neuropathy [37].

According to these reactions, researchers have put forward mechanisms by which AGEs lead to diabetic complications: (1) the accumulation of AGEs in the extracellular matrix causing aberrant crosslinking, resulting in a decrease of elasticity of vessels; (2) intracellular AGEs formation leading to quenching of nitric oxide and impaired function of growth factors [20]; (3) the binding of AGEs to AGE-receptors on different cell types and activation of key cell signaling pathways such as NF-kB activation with subsequent modulation of gene expression in vascular cells such as endothelial cells, smooth muscle cells, and macrophages [38].
