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      The Fibronectin Production Is Increased by Thrombospondin via Activation of TGF-β in Cultured Human Mesangial Cells



      S. Karger AG

      Mesangial cells, Diabetic nephropathy, Thrombospondin, Transforming growth factor beta, Fibronectin

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          Thrombospondin (TSP) is a multifunctional glycoprotein that is synthesized by a variety of cells including mesangial cells (MCs). To clarify the effect of TSP on the pathogenesis of diabetic nephropathy, we studied the effect of glucose concentrations on TSP synthesis in cultured human MCs. Thereafter, the effects of TSP on the activation of transforming growth factor beta (TGF-β) and fibronectin production were investigated in MCs. Incubating MCs with elevated glucose levels for 6 days resulted in an increase in TSP synthesis, measured by an enzyme-linked immunosorbent assay, both in culture media and cell layers. Treatment of MCs with TSP (final concentrations 1 and 5 µg/ml) for 24 h resulted in an increase (1.3- and 2.1-fold, respectively) in active TGF-β, which was determined with an enzyme-linked immunosorbent assay using TGF-β-soluble receptor type II, in the culture media without having any effect on the production of total TGF-β. Exposure of MCs to TSP caused enhancement of fibronectin production in both media and cell layers in a TSP dose-dependent manner with the maximum at a TSP concentration of 1 µg/ml. The TSP-induced increase in fibronectin production from MCs was completely prevented by concomitant treatment with 10 µg/ml anti-TGF-β neutralizing antibody. These results indicate that the TSP production is promoted by a high ambient glucose concentration in human MCs and that TSP, in turn, causes an increase in fibronectin production via activation of TGF-β.

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          Most cited references 2

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          Thrombospondin causes activation of latent transforming growth factor- beta secreted by endothelial cells by a novel mechanism [published erratum appears in J Cell Biol 1993 Sep;122(5):following 1143]

          Thrombospondin (TSP) forms specific complexes with transforming growth factor-beta (TGF-beta) in the alpha granule releasate of platelets and these TSP-TGF-beta complexes inhibit the growth of bovine aortic endothelial cells (BAE). In these studies, we report that TSP stripped of associated TGF-beta (sTSP) retained growth inhibitory activity which was partially reversed by a neutralizing antibody specific for TGF- beta. Since BAE cells secrete latent TGF-beta, we determined whether sTSP activates the latent TGF-beta secreted by BAE cells. Cells were cultured with or without sTSP and then the conditioned medium was tested for the ability to support TGF-beta-dependent normal rat kidney (NRK) colony formation in soft agar. Medium conditioned with sTSP showed a dose- and time-dependent ability to stimulate BAE-secreted TGF- beta activity, reaching maximal activation by 1-2 h with 0.4 micrograms/ml (0.9 nM) sTSP. The sTSP-mediated stimulation of TGF-beta activity is not dependent on serum factors and is not a general property of extracellular matrix molecules. The sTSP-mediated stimulation of TGF-beta activity was blocked by a mAb specific for sTSP and by neutralizing antibodies to TGF-beta. Activation of BAE cell secreted latent TGF-beta by sTSP can occur in the absence of cells and apparently does not require interactions with cell surface molecules, since in conditioned medium removed from cells and then incubated with sTSP, activation occurs with kinetics and at levels similar to what is seen when sTSP is incubated in the presence of cells. Serine proteases such as plasmin are not involved in sTSP-mediated activation of TGF- beta. Factors that regulate the conversion of latent to active TGF-beta are keys to controlling TGF-beta activity. These data suggest that TSP is a potent physiologic regulator of TGF-beta activation.
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            Role for carbohydrate structures in TGF-beta 1 latency.

            Transforming growth factor-beta (TGF-beta) (reviewed in refs 1-3) is a family of molecules that are made up as disulphide-bonded dimers of at least three different types of homologous polypeptides. The active molecules are cleaved from the C termini of precursors. TGF-beta 1, like other forms of TGF-beta, is synthesized and secreted in a latent high relative molecular mass form (L-TGF-beta 1) from which active TGF-beta 1 can be released by transient and probably unphysiological acidification. The latent complex from human platelets contains one dimeric TGF-beta 1 molecules, which is noncovalently associated with a disulphide-bonded complex of one dimeric remnant of the precursor and a single molecule of the so-called TGF-beta 1 binding protein (TGF-beta 1-BP). We report here that enzymatic removal in vitro of the carbohydrate structures in the remnant of the TGF-beta 1 precursor produces biologically active TGF-beta 1 from the latent complex, suggesting that carbohydrate structures are of importance in rendering TGF-beta 1 inactive in the complex in vivo.

              Author and article information

              S. Karger AG
              May 1998
              29 April 1998
              : 79
              : 1
              : 38-43
              2nd Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan
              44989 Nephron 1998;79:38–43
              © 1998 S. Karger AG, Basel

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              Figures: 3, Tables: 2, References: 41, Pages: 6
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