Heparanase is a key player in renal fibrosis by regulating TGF-β expression and activity

Giovanni Gambaro, Valentina Masola, Gianluigi Zaza, Maria Francesca Secchi, Antonio Lupo, Maurizio Onisto

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

42 Citazioni (Scopus)

Abstract

Epithelial-mesenchymal transition (EMT) of tubular cells is one of the mechanisms which contribute to renal fibrosis and transforming growth factor-β (TGF-β) is one of the main triggers. Heparanase (HPSE) is an endo-β-D-glucuronidase that cleaves heparan-sulfate thus regulating the bioavailability of growth factors (FGF-2, TGF-β). HPSE controls FGF-2-induced EMT in tubular cells and is necessary for the development of diabetic nephropathy in mice. The aim of this study was to investigate whether HPSE can modulate the expression and the effects of TGF-β in tubular cells. First we proved that the lack of HPSE or its inhibition prevents the increased synthesis of TGF-β by tubular cells in response to pro-fibrotic stimuli such as FGF-2, advanced glycosylation end products (AGE) and albumin overload. Second, since TGF-β may derive from sources different from tubular cells, we investigated whether HPSE modulates tubular cell response to exogenous TGF-β. HPSE does not prevent EMT induced by TGF-β although it slows its onset; indeed in HPSE-silenced cells the acquisition of a mesenchymal phenotype does not develop as quickly as in wt cells. Additionally, TGF-β induces an autocrine loop to sustain its signal, whereas the lack of HPSE partially interferes with this autocrine loop. Overall these data confirm that HPSE is a key player in renal fibrosis since it interacts with the regulation and the effects of TGF-β. HPSE is needed for pathological TGF-β overexpression in response to pro-fibrotic factors. Furthermore, HPSE modulates TGF-β-induced EMT: the lack of HPSE delays tubular cell transdifferentiation, and impairs the TGF-β autocrine loop.
Lingua originaleEnglish
pagine (da-a)2122-2128
Numero di pagine7
RivistaBIOCHIMICA ET BIOPHYSICA ACTA
Volume1843
DOI
Stato di pubblicazionePubblicato - 2014

Keywords

  • Actins
  • Animals
  • Autocrine Communication
  • Biological Markers
  • Cell Line
  • Epithelial–mesenchymal transition
  • Fibronectins
  • Fibrosis
  • Gene Expression Regulation
  • Glucuronidase
  • Heparanase
  • Humans
  • Kidney
  • Matrix Metalloproteinase 9
  • Mesoderm
  • Mice
  • Renal fibrosis
  • TGF-β
  • Transforming Growth Factor beta
  • Vimentin

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