Thrombospondin-1 is the key activator of TGF-beta1 in human mesangial cells exposed to high glucose.
Elevated levels of transforming growth factor-beta1 (TGF-beta1) 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-beta1 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-beta1. 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-beta1 to bioactive growth factor over 3 wk of exposure of mesangial cells to 30 mM D-glucose. Peptide inhibition of TGF-beta1 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-beta1 activation, and normalized expression of FN.
Molecular Pathology Section, Division of Biomedical Sciences, Imperial College School of Medicine, London, United Kingdom.
Natalia
N
Yevdokimova
Molecular Pathology Section, Division of Biomedical Sciences, Imperial College School of Medicine, London, United Kingdom.
Nadia Abdel
NA
Wahab
Molecular Pathology Section, Division of Biomedical Sciences, Imperial College School of Medicine, London, United Kingdom.
Roger M
RM
Mason
D004305:Dose-Response Relationship, Drug; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
D005353:Fibronectins; C105465:KLF6 protein, human; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D016376:Oligonucleotides, Antisense; D009842:Oligopeptides; D017395:Plasminogen Activator Inhibitor 1; D011518:Proto-Oncogene Proteins; C508960:TGFB1 protein, human; D019700:Thrombospondin 1; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C430603:glycyl-glycyl-tryptophyl-seryl-histidyl-tryptophan; D005947:Glucose