Advanced Glycation End Products and Receptor for Advanced Glycation End Products in AA Amyloidosis

Abstract

Advanced glycation end products (AGEs) may be involved in either amyloidogenesis or complications related to amyloid. We hypothesized that AGEs may influence the pathogenesis of AA amyloidosis, and investigated the spatial and temporal relationship between AGEs, carboxy methyl lysine (CML), the AGE receptor (RAGE), and AA amyloid in humans and mice. Specimens from patients with AL and ATTR amyloidosis served as a control. Using immunohistochemistry, AGEs, CML, and RAGE were found within amyloid deposits, more commonly in AA amyloid than in AL amyloid and not in ATTR amyloid. Western blotting showed that multiple proteins (between 12 and >60 kd) are modified, but not the AA amyloid fibril protein itself. In the murine model of AA amyloidosis, we found a marked interindividual variability with respect to local and systemic CML levels, as well as to splenic RAGE transcription. Serum levels of CML correlated with the duration of the inflammatory response but not with amounts of splenic RAGE mRNA. Other as yet unidentified variables, especially of the heterogeneous group of AGEs, probably modulate transcription of RAGE and influence amyloidogenesis. CML serum levels, in turn, may prove useful in predicting patients at risk. Advanced glycation end products (AGEs) formed by nonenzymatic glycoxidation of proteins and lipids have been implicated in complications contributing to the increased morbidity and mortality of patients suffering from diabetes and uremia. Hyperglycemia in diabetic patients, and oxidative stress and carbonyl stress in uremic patients, contribute to the formation of AGEs, which are a chemically heterogeneous group of stable covalently bound and cross-linked adducts.

Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds

“…Glycoxidative modification is associated with both aging and diabetes and appears to lead to the renal deposition of amyloid material [48]. Formation of AGEs is involved in the onset of amyloidosis and related complications [49]. In addition, amyloid is also a ligand for RAGE, and RAGE is known as a propagation factor in amyloidogenesis [50].…”

Molecular pathology and age estimation

“…These methods include enzyme linked immunosorbent assays (ELISA) applying either polyclonal or monoclonal antibodies [135,1,136], immunohistochemistry [1,137] HPLC [138][139][140], GC-MS [141,142] or fluorimetry using the autofluorescent properties of AGEs [143]. In addition, MALDI-TOF and LC-MS-approaches have been described with the advantages of detecting minute amounts [144,145].…”

Receptor for advanced glycation endproducts and progressive kidney disease

“…Serum levels of AGEs have been found to be increased in patients with chronic rheumatoid arthritis (RA) with amyloid A-type amyloidosis, compared with those with non-amyloid A-type amyloidosis [63]. Further, AGEs accumulation and RAGE expression were enhanced in the amyloid deposits of the glomeruli in patients with amyloid A-type amyloidosis [64]. In addition, serum levels of AGEs are increased in familial amyloidotic polyneuropathy (FAP) patients compared with agematched healthy controls [10].…”