Advanced glycation end products: A nephrologist's perspective

Advanced glycation end products (AGEs) are a heterogeneous group of molecul es that accumulate in plasma and tissues with advancing age, diabetes, and renal failure. There is emerging evidence that AGEs are potential uremic to xins and may have a role in the pathogenesis of vascular and renal complica tions associated with diabetes and aging. AGEs are formed when a carbonyl o f a reducing sugar condenses with a reactive amino group in target protein. These toxic molecules interact with specific receptors and elicit pleiotro pic responses. AGEs accelerate atherosclerosis through cross-linking of pro teins, modification of matrix components, platelet aggregation, defective v ascular relaxation, and abnormal lipoprotein metabolism. In vivo and in vit ro studies indicate that AGEs have a vital role in the pathogenesis of diab etic nephropathy and the progression of renal failure. The complications of normal aging, such as loss of renal function, Alzheimer's disease, skin ch anges, and cataracts, may also be mediated by progressive glycation of long -lived proteins. AGEs accumulate in renal failure as a result of decreased excretion and increased generation resulting from oxidative and carbonyl st ress of uremia. AGE modified beta(2)-microglobulin is the principal pathoge nic component of dialysis-related amyloidosis in patients undergoing dialys is, Available dialytic modalities are not capable of normalizing AGE levels in patients with end-stage renal disease. A number of reports indicated th at restoration of euglycemia with islet-cell transplantation normalized and prevented further glycosylation of proteins. Aminoguanidine (AGN), a nucle ophilic compound, not only decreases the formation of AGEs but also inhibit s their action. A number of studies have shown that treatment with AGN impr oves neuropathy and delays the onset of retinopathy and nephropathy. N-Phen acylthiazolium bromide is a prototype AGE cross-link breaker that reacts wi th and can cleave covalent AGE-derived protein cross-links. Thus, there is an exciting possibility that the complications of diabetes, uremia, and agi ng may be prevented with these novel agents. (C) 2000 by the National Kidne y Foundation, Inc.