oxidative stress. Hemoglobin-AGE levels are elevated in diabetic individuals and other AGE proteins have been shown in experimental models to accumulate with time, increasing from 5-50 fold over periods of 5–20 weeks in the retina, lens and renal cortex of diabetic rats. The inhibition of AGE formation reduced the extent of nephropathy in diabetic rats. Therefore, substances that inhibit AGE formation may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGE-mediated disease. AGEs have specific cellular receptors; the best-characterized are those called RAGE. The activation of cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers the generation of free radicals and the expression of inflammatory gene mediators. Such increases in oxidative stress lead to the activation of the transcription factor NF-κB and promote the expression of NF-κB regulated genes that have been associated with atherosclerosis. Reactivity Proteins are usually glycated through their lysine residues. In humans, histones in the cell nucleus are richest in lysine, and therefore form the glycated protein N(6)-Carboxymethyllysine (CML). A receptor nicknamed RAGE, from receptor for advanced glycation end products, is found on many cells, including endothelial cells, smooth muscle, cells of the immune system from tissue such as lung, liver, and kidney. This receptor, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy, periodontitis and neuropathy. The pathogenesis of this process hypothesized to activation of the nuclear factor kappa B (NF-κB) following AGE binding. NF-κB controls several genes which are involved in inflammation. Clearance In clearance, or the rate at which a substance is removed or cleared from the body, it has been found that the cellular proteolysis of AGEs—the breakdown of proteins—produces AGE peptides and "AGE free adducts" (AGE adducts bound to single amino acids). These latter, after being released into the plasma, can be excreted in the urine. Nevertheless, the resistance of extracellular matrix proteins to proteolysis renders their advanced glycation end products less conducive to being eliminated. While the AGE free adducts are released directly into the urine, AGE peptides are endocytosed by the epithelial cells of the proximal tubule and then degraded by the endolysosomal system to produce AGE amino acids. It is thought that these acids are then returned to the kidney's inside space, or lumen, for excretion. AGE free adducts are the major form through which AGEs are excreted