Advanced glycation end products (AGEs) formed from glyceraldehyde (Gcer) and glycolaldehyde (Gcol) are involved in the pathogenesis of diabetic complications, via interactions with a receptor for AGEs (RAGE). In this study, we aimed to elucidate the RAGE-binding structure in Gcer and Gcol-derived AGEs and identify the minimal moiety recognized by RAGE. Among Gcer and Gcol-derived AGEs, GLAP (glyceraldehyde-derived pyridinium) and GA-pyridine elicited toxicity in PC12 neuronal cells. The toxic effects of GLAP and GA-pyridine were suppressed in the presence of anti-RAGE antibody or the soluble form of RAGE protein. Furthermore, the cytotoxicity test using GLAP analog compounds indicated that the 3-hydroxypyridinium (3-HP) structure is sufficient for RAGE-dependent toxicity. Surface plasmon resonance analysis showed that 3-HP derivatives directly interact with RAGE. These results indicate that GLAP and GA-pyridine are RAGE-binding epitopes, and that 3-HP, a common moiety of GLAP and GA-pyridine, is essential for the interaction with RAGE.
Keywords: 3-HP: 3-hydroxypyridinium; 3-Hydroxypyridinium; AGEs: advanced glycation end products; Advanced glycation end products; DAPI: 6-diamidino-2-phenylindole; GST: glutathione S-transferase; Gcer: glyceraldehyde; Gcol: glycolaldehyde; NAC: N-acetylcysteine; RAGE: receptor for advanced glycation end products; ROS: reactive oxygen species; SPR: surface plasmon resonance; glyceraldehyde; glycolaldehyde; receptor for advanced glycation end products.