Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/dbmouse

Albumin modified by Amadori glucose adducts stimulates the expression of ex tracellular matrix proteins by glomerular mesangial and endothelial cells, and has been mechanistically linked to the pathogenesis of diabetic nephrop athy. To test the hypothesis that inhibiting the formation of glycated albu min might beneficially influence the development of kidney disease in diabe tes, we treated diabetic db/db mice for 12 weeks with a low-molecular-weigh t compound (EXO-226) that impedes the condensation of free glucose with lys ine E-amino groups in albumin. Administration of EXO-226 (3 mg/kg) twice da ily by gavage normalized the plasma concentration of glycated albumin withi n days after initiation of treatment and maintained glycated albumin within the normal range throughout the study, despite persistent and severe hyper glycemia. Urine albumin excretion, which was markedly increased at the star t of the study (age 12 weeks), was significantly reduced in treated diabeti c animals compared with their untreated diabetic littermates. The fall in c reatinine clearance that was observed in untreated diabetic animals was pre vented in diabetic littermates that received treatment. Compared with the n ondiabetic controls, the amount of glomerular mesangial matrix was threefol d greater in untreated diabetic mice; in contrast, the mesangial matrix fra ction was only 1.5 times that of nondiabetic controls in the treated diabet ic animals, representing a reduction in mesangial matrix accumulation of mo re than 50%. EXO-226 also reduced the overexpression of mRNA encoding for a l (IV) collagen in renal cortex of db/db mice. We conclude that normalizati on of plasma glycated albumin concentrations with the glycation inhibitor E XO-226 ameliorates the glomerular structural and functional abnormalities a ssociated with diabetic nephropathy in the db/db mouse. Copyright (C) 2000 S. Karger AG, Basel.