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J Am Soc Nephrol 12:703-712, 2001
© 2001 American Society of Nephrology

Thrombospondin-1 Is the Key Activator of TGF-ß1 in Human Mesangial Cells Exposed to High Glucose

NATALIA YEVDOKIMOVA, NADIA ABDEL WAHAB and ROGER M. MASON

Molecular Pathology Section, Division of Biomedical Sciences, Imperial College School of Medicine, London, United Kingdom.

Correspondence to Professor Roger M. Mason, Molecular Pathology Section, Division of Biomedical Sciences, Imperial College School of Medicine, Sir Alexander Fleming Building, Exhibition Road, South Kensington, London, SW7 2AZ, UK. Phone: +44 20 7594 3019; Fax: +44 20 7594 3022; E-mail: roger.mason{at}ic.ac.uk

Abstract. Elevated levels of transforming growth factor-ß1 (TGF-ß1) are synthesized by human mesangial cells that are cultured in medium that contains high concentrations of glucose and mediate increased synthesis of fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1), and changes in the expression of other genes. TGF-ß1 is synthesized as a latent complex. Previous work indicated that high-glucose conditions also upregulate expression of thrombospondin-1 (TSP-1), a potential activator of latent TGF-ß1. With the use of the synthetic peptide GGWSHW, an inhibitor of the TSP-1 activation mechanism, endogenous TSP-1 is shown to be responsible for converting high levels of latent TGF-ß1 to bioactive growth factor over 3 wk of exposure of mesangial cells to 30 mM D-glucose. Peptide inhibition of TGF-ß1 activation by TSP-1 in high-glucose conditions completely suppressed increases in FN and PAI-1 expression. Treating mesangial cells maintained in high glucose with a TSP-1 antisense oligonucleotide reduced TSP-1 expression to levels found in 4 mM D-glucose cultures, prevented TGF-ß1 activation, and normalized expression of FN.




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