Glucose stimulation of transforming growth factor-beta bioactivity in mesangial cells is mediated by thrombospondin-1.
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-beta (TGF-beta). Previously we showed that thrombospondin-1 (TSP-1) activates latent TGF-beta both in vitro and in vivo. Activation occurs as the result of specific interactions of latent TGF-beta with TSP-1, which potentially alter the conformation of latent TGF-beta. As glucose also up-regulates TSP-1 expression, we hypothesized that the increased TGF-beta bioactivity observed in rat and human mesangial cells cultured with high glucose concentrations is the result of latent TGF-beta activation by autocrine TSP-1. Glucose-induced bioactivity of TGF-beta in mesangial cell cultures was reduced to basal levels by peptides from two different sequences that antagonize activation of latent TGF-beta 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-beta activity and the resultant matrix protein synthesis are dependent on the action of autocrine TSP-1 to convert latent TGF-beta to its biologically active form. These data suggest that antagonists of TSP-dependent TGF-beta activation may be the basis of novel therapeutic approaches for ameliorating diabetic renal fibrosis.
Poczatek
M H
MH
Department of Pathology, Division of Molecular and Cellular Pathology, and The Cell Adhesion and Matrix Research Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Hugo
C
C
Darley-Usmar
V
V
Murphy-Ullrich
J E
JE
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008907:Mink; D051381:Rats; D019700:Thrombospondin 1 / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
D016326:Extracellular Matrix Proteins; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D005947:Glucose