Dietary glycotoxins - Inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration

Evidence indicates that the metabolic turnover of food-derived reactive ora lly absorbed advanced glycation end products (AGEs) or glycotoxins (GTs) is delayed, possibly contributing to the tissue damage induced by endogenous AGEs, especially in patients with diabetes and kidney disease. The aim of t his study was to explore whether pharmacologic inhibition of dietary AGE bi oreactivity by aminoguanidine (AG) can improve turnover and renal excretion of these substances. Normal Sprague-Dawley rats were fed single-labeled [C -14]AGE-ovalbumin, double-labeled [C-14-I-125]AGE-ovalbumin, or control I-1 25-labeled ovalbumin diet plus free [C-14]glucose, with or without AG (0.2% in water). [C-14]AGE- and I-125-labeled peptide-associated radioactivity ( RA) were compared with AGE immunoreactivity (by enzyme-linked immunosorbent assay) in tissues, serum, and 72-h urine samples. The effect of AG on diet ary AGE bioreactivity was assessed by monitoring the inhibition of covalent complex formation between fibronectin (FN) peptide fragments and serum com ponents, after a meal of labeled dietary AGE with or without AG. The radiol abeled AGE diet produced serum absorption and urinary excretion peaks kinet ically distinct from those of free [C-14]glucose or [I-125]ovalbumin. Some 26% of the orally absorbed AGE-ovalbumin was excreted in the urine, whereas after AG treatment, urinary excre-tion of dietary AGEs increased markedly (to >50% of absorbed). More than 60% of tissue-bound RA was found covalentl y deposited in kidneys and liver, whereas after treatment with AG, tissue A GE deposits were reduced to <15% of the amount found in untreated AGE-fed c ontrols. Sera enriched for dietary GTs formed covalently linked complexes w ith FN, a process completely inhibitable by AG cotreatment. Amelioration of dietary GT bioreactivity by AG improves renal elimination and prevents tis sue deposition of food GTs. This may afford a novel and potentially protect ive use of AG against excessive tissue AGE toxicity in diabetic patients wi th renal disease.