Do changes in transglutaminase activity alter latent transforming growth factor beta activation in experimental diabetic nephropathy?

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Authors

  • Linghong Huang
  • John L. Haylor
  • Marie Fisher
  • Zoe Hau
  • A. Meguid El Nahas
  • Martin Griffin
  • Timothy S. Johnson

Research units

Abstract

Background. Diabetic nephropathy is the leading cause of end-stage kidney failure worldwide. It is characterized by excessive extracellular matrix accumulation. Transforming growth factor beta 1 (TGF-ß1) is a fibrogenic cytokine playing a major role in the healing process and scarring by regulating extracellular matrix turnover, cell proliferation and epithelial mesanchymal transdifferentiation. Newly synthesized TGF-ß is released as a latent, biologically inactive complex. The cross-linking of the large latent TGF-ß to the extracellular matrix by transglutaminase 2 (TG2) is one of the key mechanisms of recruitment and activation of this cytokine. TG2 is an enzyme catalyzing an acyl transfer reaction leading to the formation of a stable e(?-glutamyl)-lysine cross-link between peptides.Methods. To investigate if changes in TG activity can modulate TGF-ß1 activation, we used the mink lung cell bioassay to assess TGF-ß activity in the streptozotocin model of diabetic nephropathy treated with TG inhibitor NTU281 and in TG2 overexpressing opossum kidney (OK) proximal tubular epithelial cells.Results. Application of the site-directed TG inhibitor NTU281 caused a 25% reduction in kidney levels of active TGF-ß1. Specific upregulation of TG2 in OK proximal tubular epithelial cells increased latent TGF-ß recruitment and activation by 20.7% and 19.7%, respectively, in co-cultures with latent TGF-ß binding protein producing fibroblasts.Conclusions. Regulation of TG2 directly influences the level of active TGF-ß1, and thus, TG inhibition may exert a renoprotective effect by targeting not only a direct extracellular matrix deposition but also TGF-ß1 activation and recruitment.

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Details

Original languageEnglish
Pages (from-to)3897-3910
Number of pages14
JournalNephrology, Dialysis, Transplantation
Volume25
Issue number12
Early online date26 May 2010
DOIs
Publication statusPublished - Dec 2010

    Keywords

  • animals, coculture techniques, experimental diabetes mellitus, diabetic nephropathies, animal disease models, enzyme inhibitors, fibrosis, GTP-binding proteins, proximal kidney tubules, male, mice, mink, opossums, protein isoforms, rats, wistar rats, streptozocin, swiss 3T3 cells, transfection, transforming growth factor beta1, transforming growth factor beta2, transforming growth factor beta3, transglutaminases

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