Effects of glycated type IV collagen on extracellular matrix components synthesis in rat mesangial cells

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Recent studies have indicated that increased glycation in glomerular proteins plays an important role in the pathogenesis of diabetic nephropathy. Type IV collagen, one of major components of glomerular extracellular matrix, appears to be a predominant targets for protein glycation because of its long half life. Diabetic nephropathy is characterized by the accumulation of mesangial matrix. Accumulation of mesangial matrix occurs as the result of an increase in production of matrix components or a decrease in matrix degradation, and recent studies indicates a preeminent role for TGF-beta in the accumulation of mesangial matrix. To clarify the role of accumulation of glacycated type IV collagen in the development of glmerular sclerosis, we investigated that the effects of in vitro glycation of type IV collagen on the gene expression of matrix components, matrix-degrading enzyme, and TGF-beta in rat mesangial cells.Type IV collagen was glycated with incubation with glucose. Addition of gl … More ycated type IV collagen to meangial cells caused time dependent increase in the alpha1(I) collagen mRNA levels with maximal increases occurring at 48 hr. Addition of glycated type IV collagen also led to increases in mRNA levels for alpha1(IV) collagen and fibronectin. Gelatinolytic activity in conditioned media was not affected by the addition of glycated type IV collagen. The mRNA levels for matrix metalloproteinase-2 also did not show significant change by the glycated type IV collagen. Glycated type IV collagen induced increase in TGF-beta mRNA levels after 24 hr, which preceded the increase in alpha1(I) collagen mRNA levels. Increase in alpha1(I) collagen mRNA levels induced by glycated coll IV was significantly decreased by the co-incubation with anti-TGF-beta neutralizing antibody. Transient transfections of mesangial cells with alpha1(I) collagen promoter-luciferase constructs showed significant increase in promoter activity by the addition of glycated type IV collagen.These results indicated that glycated type IV collagen induces matrix components gene expression through transcriptional activation in mensangial cells and these effects are mediated in part by the induction of TGF-beta expression. Less