GLYCATED ALBUMIN STIMULATES FIBRONECTIN GENE-EXPRESSION IN GLOMERULARMESANGIAL CELLS - INVOLVEMENT OF THE TRANSFORMING-GROWTH-FACTOR-BETA SYSTEM

Albumin modified by Amadori glucose adducts, formed in increased amoun ts in diabetes, stimulates collagen IV production and gene expression in renal glomerular mesangial cells, and induces mesangial matrix accu mulation accompanied by increased mRNA encoding alpha(1) (IV) collagen and fibronectin in diabetic animals. These effects contribute to the pathogenesis of diabetic nephropathy, and resemble biologic activities of the cytokine TGF-beta(1), which also has been causally implicated in diabetic renal disease. We postulated that Amadori-modified glycate d albumin modulates TGF-beta(1) expression in mesangial cells, and tha t TGF-beta(1) participates in mediating the glycated albumin-induced i ncreases in mesangial cell matrix production. To test this hypothesis, we measured mRNA encoding TGF-beta(1), the TGF-beta Type II receptor and fibronectin, a key matrix component of the TGF-beta(1) tissue resp onse, after incubation of mesangial cells with glycated albumin. Stead y state levels of the mRNAs encoding for these proteins were stimulate d when mesangial cells were cultured in the presence of albumin contai ning Amadori glucose adducts compared with levels in cells cultured wi th the nonglycated, glucose-free counterpart. The glycated protein-ind uced changes in mRNA expression were observed with concentrations of g lycated albumin encompassing those found in clinical specimens and in media containing physiologic (5.5 mM) glucose concentrations, indicati ng that they were due to the glucose-modified protein and not to a hyp erglycemic milieu. Further, they were accompanied by increased transla ted fibronectin protein, which was prevented with TCF-beta neutralizin g antibody, as was the glycated albumin-induced increase in fibronecti n mRNA. The findings indicate that Amadori-modified glycated albumin s timulates mesangial cell TGF-beta(1) gene expression by mechanisms tha t are operative under normoglycemic conditions. These data provide the first link between elevated glycated serum albumin concentrations and increased TGF-beta(1) bioactivity in the pathogenesis of mesangial ma trix accumulation in diabetes.