Advanced glycosylation endproducts in diabetic renal disease: clinical measurement, pathophysiological significance, and prospects for pharmacological inhibition.

Glucose reacts nonenzymatically with amino groups to produce a class of stable, crosslinking moieties termed advanced glycosylation endproducts (AGEs). These products act to increase vascular permeability, enhance subintimal protein and lipoprotein deposition, inactivate nitric oxide, and exert a number of toxic effects of endothelial cells. Loss of normal renal function has been found recently to cause a marked increase in the circulating levels of plasma AGEs, suggesting that these moieties may comprise one component of the so-called uremic 'middle molecules'. AGEs also form on the lipid and the protein components of LDL, forming a modified form of LDL (AGE-LDL) which is not taken up by tissue LDL receptors. Aminoguanidine offers a specific therapeutic modality for inhibiting advanced glycosylation in vivo and has been observed recently to reduce both hemoglobin-AGE and circulating LDL levels.