THE PATHOGENIC POTENTIAL OF DIFFERENT SIZED AGE MODIFIED MOLECULES VIA RAGE SIGNALLING PATHWAYS

摘要

Advanced glycation end-products (AGEs) are a heterogenous group of modifications on proteins that are formed as a result of non-enzymatic reactions, including the Maillard reaction. The formation of AGEs is accelerated under diabetic conditions due to chronic hyperglycemia, oxidative stress and diminished clearance of AGE precursors. Therapeutic inhibition of AGE formation is known to reduce cellular dysfunction and the progression of diabetic complications, including kidney disease. AGEs have a wide range of chemical, cellular, and tissue effects that contribute to the development and progression of diabetic complications. Some of these effects are mediated via binding to the receptor for AGE (RAGE) and activation of downstream signalling pathways including oxidative stress, nuclear factor kB (NFkB), protein kinase C (PKC), and vascular endothelial growth factor (VEGF) and each may promote the formation of AGEs in the vicious cycle associated with progressive kidney damage. RAGE is also activated by a range of other ligands, including the pro-inflammatory calcium-binding S100/calgranulins, high-mobility group box 1 (HMGB1), and β-amyloid sheets. The purpose of this study was to investigate the activation of RAGE-dependent signalling pathways in primary renal mesangial cells by different RAGE ligands including AGE peptides and AGE modified proteins, calcium-binding S100 proteins and HMGB1