EFFECTS OF GLYCATED ALBUMIN ON MESANGIAL CELLS - EVIDENCE FOR A ROLE IN DIABETIC NEPHROPATHY

Nonenzymatically glycated proteins are preferentially transported acro ss the glomerular filtration barrier, and the glomerular mesangium in diabetes is bathed with serum containing increased concentrations of g lycated albumin. We investigated effects of glycated albumin on mesang ial cells, which are involved in diabetic nephropathy. [H-3]-thymidine incorporation was significantly inhibited when murine mesangial cells were grown in culture media containing human serum that had been none nzymatically glycated by incubation for 4 days with 28 mM glucose. Thi s inhibition was reversed when monoclonal antibodies that selectively react with Amadori products of glycated albumin were added to the cult ure media. Purified glycated albumin containing Amadori adducts of the glycation reaction induced significant inhibition of thymidine incorp oration and stimulation of Type IV collagen secretion compared with ce lls cultured in the presence of purified nonglycated albumin. These ch anges were prevented when monoclonal antibodies specifically reactive with fructosyl-lysine epitopes in glycated albumin were added to the c ultures. The antibodies had no effect on growth or collagen production in the presence of nonglycated albumin. The results provide the first evidence directly implicating Amadori adducts in glycated albumin in the pathogenesis of diabetic nephropathy, which is characterized by de creased cellularity in association with expansion of the mesangial mat rix.