Advanced glycation end products and the progressive course of renal disease

In experimental and human diabetic nephropathy (DN), It has been shown that advanced glycation end products (AGEs), In particular, carboxymethyl-lysin e and pentosidine, accumulate with malondialdehyde In glomerular lesions In relation to disease severity and in the presence of an upregulated recepto r for AGE (RAGE) in podocytes. Toxic effects of AGEs result from structural and functional alterations in plasma and extracellular matrix (ECM) protei ns, In particular, from cross-linking of proteins and interaction of AGEs w ith their receptors and/or binding proteins. In mesangial and endothelial c ells, the AGE-RAGE interaction caused enhanced formation of oxygen radicals with subsequent activation of nuclear factor-kappaB and release of pro-inf lammatory cytokines (interleukin-6, tumor necrosis factor-alpha), growth fa ctors (transforming growth factor-beta1 [TGF-beta1], insulin-like growth fa ctor-1), and adhesion molecules (vascular cell adhesion molecule-1, interce llular adhesion molecule-1). In tubular cells, incubation with AGE albumin was followed by stimulation of the mitogen-activating protein (MAP) kinase pathway and its downstream target, the activating protlen-1 (AP-1) complex, TGF-beta1 overexpression, enhanced protein kinase C activity, decreased ce ll proliferation, and Impaired protein degradation rate, in part caused by decreased cathepsin activities. The pathogenic relevance of AGEs was furthe r verified by in vivo experiments in euglycemic rats and mice by the parent eral administration of AGE albumin, leading in the glomeruli to TGF-beta1 o verproduction, enhanced gene expression of ECM proteins, and morphological lesions similar to those of DN. Evidence for the pathogenic relevance of AG Es in DN also comes from experimental studies in which the formation and/or action of AGEs was modulated by aminoguanidine, OPB-9195, pyridoxamine, so luble RAGEs, serine protease trypsin, and antioxidants, resulting in Improv ed cell and/or renal function. (C) 2001 by the National Kidney Foundation, Inc.