ROLE OF AMADORI-MODIFIED NONENZYMATICALLY GLYCATED SERUM-PROTEINS IN THE PATHOGENESIS OF DIABETIC NEPHROPATHY

Accelerated nonenzymatic glycation in diabetes, resulting in Amadori-m odified proteins and the later-developing advanced glycation end-produ cts, has been mechanistically linked to the pathogenesis of diabetic n ephropathy. Recent focus on putative AGE-induced pathophysiology has s hifted attention from the possible role of Amadori-modified proteins i n the development of diabetic complications, Ample experimental eviden ce has demonstrated that Amadori-modified serum proteins adversely aff ect renal glomerular capillary function, structure, and metabolism. Pr evious studies from the laboratories of this study's authors have show n that human serum containing diabetic concentrations of albumin modif ied by Amadori-glucose adducts inhibits the replication of murine mesa ngial cells in culture and stimulates the production and gene expressi on of type IV collagen, Monoclonal antibodies (A717) specific for Amad ori-glycated albumin prevent these abnormalities, In other studies, it has also been shown that in vivo administration of A717 (Fab fragment s) retards the progression of diabetic nephropathy in diabetic db/db m ice, Neutralizing the effects of the elevated circulating glycated alb umin concentration is associated with reduction in proteinuria and mes angial matrix expansion, and prevention of the overexpression of mRNA encoding type IV collagen and fibronectin in the renal cortex, The ren oprotective effects of A717 are independent of any change in blood glu cose concentrations. These studies implicate Amadori-modified glycated albumin in the pathogenesis of diabetic nephropathy, It is proposed i n this study that abrogating the biologic effects of increased glycate d albumin in diabetes has novel therapeutic potential in the managemen t of diabetic renal complications.