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15 Transitory effect of circulating glycated albumin on glomerular filtration properties

During hyperglycemia, serum and tissue proteins can be modified by glycation, the non-enzymatic covalent attachment of glucose residues to basic aminoacids. The presence of circulating modified proteins in diabetic subjects seems to be directly involved in the pathogenesis of diabetic nephropathy. Our studies have demonstrated differences in renal handling of non-glycated (BSA) and glycated (gBSA) albumins in the normal animal. We observed a preferential glomerular basement membrane (GBM) filtration with an impaired tubular reabsorption of gBSA as compared to BSA. Interestingly, a facilitated filtration of BSA was also detected in the presence of gBSA. The aim of the present study was to determine whether the gBSA-induced modifications of the GBM filtration properties are permanent or transitory. BSA and gBSA were covalently coupled to two different haptens, FITC and DNP, respectively. DNP-gBSA was intravenously injected to normal mice and maintained in circulation for 30 min, 1, 2, 4, 24 and 48 h. Five minutes before sacrifice, the FITC-BSA was injected. Renal cortexes were fixed in aldehydes and osmium and embedded in Epon. The tracers were detected by immunocytochemistry using specific antibodies and protein A-gold. Upon morphometrical evaluations, GBM labeling distributions for FITC-BSA revealed a significant increased filtration of this form at all time points evaluated. Changes in labeling distributions after 24 and 48h were however less pronounced. Similar ratio values between gBSA labeling densities in capillary lumen and GBM were obtained at all time points suggesting that there is no accumulation of gBSA in the GBM. These results suggest that the alteration of GBM permeability to BSA in the normal mouse is due to the presence of circulating gBSA, but is gradually recovered along with the clearance of gBSA. Thus, in early diabetes, increasing concentrations of circulating glycated proteins could be responsible for the glomerular hyperfiltration and proteinuria leading to diabetic nephropathy. Supported by the Medical Research Council of Canada.

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