Renal fate of circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells

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Abstract
The presence of excessive amounts of advanced glycation end products (AGE) in tissues or in the circulation may critically affect the progression of diabetic nephropathy. Circulating AGE levels, mainly in the form of small peptides, increase in diabetic patients or in patients with end-stage renal disease. This rise correlates with the severity of the nephropathy. However, so far little is known about the fate of AGE-proteins and AGE-peptides in renal tissue, and in order to elucidate this issue we undertook the present study. AGE-bovine serum albumin (AGE-BSA) and AGE-peptides were prepared, characterized by spectrophotometry, spectrofluorometry, chromatography and SDS-PAGE. AGE-peptides reacted in vitro with LDL producing biochemical and ultrastructural modifications. Using colloidal gold post-embedding immunoelectron microscopy with an anti-AGE antibody generated in our laboratory, we followed, in a short-term kinetic study, the cellular and sub-cellular localisation of circulating AGE-products throughout the nephron. AGE-peptides or AGE-BSA were injected into otherwise normal rats and detected by protein A-gold immuno-cytochemistry after 15, 30 or 45 min of circulation. Most of the AGE- BSA was found in the lumen of capillary vessels and distributed along the endothelial side of the glomerular basement membrane. Presence on mesangial matrix was also apparent. AGE-peptides were easily filtered and actively reabsorbed by the proximal convoluted tubule. At 15 min, little labelling was found in the glomerular wall. Instead, the labelling was present in the urinary space and microvilli of epithelial cells. Early endosomes displayed intense labelling as well. At 45 min, late endosomes and lysosomes added to the pattern of labelling. The distal tubule epithelial cells were devoid of labelling for any of the intervals studied. AGE-peptides but not AGE-BSA could be detected in the urine of injected rats. These observations point to participation of the endo-lysosomal apparatus of the proximal convoluted tubule to the disposal of AGE-peptides, while giving an ultrastructural support for a key role of the kidney in AGE catabolism.

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