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From the Department of Pathology,*
Division of Molecular
and Cellular Pathology, and The Cell Adhesion and Matrix Research
Center, University of Alabama at Birmingham, Birmingham, Alabama; and
the Division of Nephrology,
Universitat
Erlangen-Nurnberg, Erlangen, Germany
Glucose is a key factor in the development of diabetic complications, including diabetic nephropathy. The development of diabetic glomerulosclerosis is dependent on the fibrogenic growth factor, transforming growth factor-ß (TGF-ß). Previously we showed that thrombospondin-1 (TSP-1) activates latent TGF-ß both in vitro and in vivo. Activation occurs as the result of specific interactions of latent TGF-ß with TSP-1, which potentially alter the conformation of latent TGF-ß. As glucose also up-regulates TSP-1 expression, we hypothesized that the increased TGF-ß bioactivity observed in rat and human mesangial cells cultured with high glucose concentrations is the result of latent TGF-ß activation by autocrine TSP-1. Glucose-induced bioactivity of TGF-ß in mesangial cell cultures was reduced to basal levels by peptides from two different sequences that antagonize activation of latent TGF-ß by TSP, but not by the plasmin inhibitor, aprotinin. Furthermore, glucose-dependent stimulation of matrix protein synthesis was inhibited by these antagonist peptides. These studies demonstrate that glucose stimulation of TGF-ß activity and the resultant matrix protein synthesis are dependent on the action of autocrine TSP-1 to convert latent TGF-ß to its biologically active form. These data suggest that antagonists of TSP-dependent TGF-ß activation may be the basis of novel therapeutic approaches for ameliorating diabetic renal fibrosis.
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