Glucose stimulation of transforming growth factor-β bioactivity in mesangial cells is mediated by thrombospondin-1

Academic Article

Abstract

  • 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-β (TGF-β). Previously we showed that thrombospondin-1 (TSP-1) activates latent TGF-β both in vitro and in vivo. Activation occurs as the result of specific interactions of latent TGF-β with TSP-1, which potentially alter the conformation of latent TGF-β. As glucose also up-regulates TSP-1 expression, we hypothesized that the increased TGF-β bioactivity observed in rat and human mesangial cells cultured with high glucose concentrations is the result of latent TGF-β activation by autocrine TSP-1. Glucose-induced bioactivity of TGF-β in mesangial cell cultures was reduced to basal levels by peptides from two different sequences that antagonize activation of latent TGF-β 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-β activity and the resultant matrix protein synthesis are dependent on the action of autocrine TSP-1 to convert latent TGF-β to its biologically active form. These data suggest that antagonists of TSP-dependent TGF-β activation may be the basis of novel therapeutic approaches for ameliorating diabetic renal fibrosis.
  • Digital Object Identifier (doi)

    Author List

  • Poczatek MH; Hugo C; Darley-Usmar V; Murphy-Ullrich JE
  • Start Page

  • 1353
  • End Page

  • 1363
  • Volume

  • 157
  • Issue

  • 4