Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells

Giovanni Gambaro, Valentina Masola, Elena Tibaldi, Anna Maria Brunati, Alessandra Gastaldello, Angela D'Angelo, Maurizio Onisto, Antonio Lupo

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71 Citazioni (Scopus)

Abstract

The epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTECs) into myofibroblasts contributes to the establishment of fibrosis that leads to end stage renal disease. FGF-2 induces EMT in PTECs. Because the interaction between FGF-2 and its receptor is mediated by heparan sulfate (HS) and syndecans, we speculated that a deranged HS/syndecans regulation impairs FGF-2 activity. Heparanase is crucial for the correct turnover of HS/syndecans. The aim of the present study was to assess the role of heparanase on epithelial-mesenchymal transition induced by FGF-2 in renal tubular cells. In human kidney 2 (HK2) PTEC cultures, although FGF-2 induces EMT in the wild-type clone, it is ineffective in heparanase-silenced cells. The FGF-2 induced EMT is through a stable activation of PI3K/AKT which is only transient in heparanase-silenced cells. In PTECs, FGF-2 induces an autocrine loop which sustains its signal through multiple mechanisms (reduction in syndecan-1, increase in heparanase, and matrix metalloproteinase 9). Thus, heparanase is necessary for FGF-2 to produce EMT in PTECs and to sustain FGF-2 intracellular signaling. Heparanase contributes to a synergistic loop for handling syndecan-1, facilitating FGF-2 induced-EMT. In conclusion, heparanase plays a role in the tubular-interstitial compartment favoring the FGF-2-dependent EMT of tubular cells. Hence, heparanase is an interesting pharmacological target for the prevention of renal fibrosis.
Lingua originaleEnglish
pagine (da-a)1478-1488
Numero di pagine11
RivistaJOURNAL OF BIOLOGICAL CHEMISTRY
Volume287
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • Autocrine Communication
  • Cell Line
  • Enzyme Activation
  • Epithelial-Mesenchymal Transition
  • Fibroblast Growth Factor 2
  • Fibrosis
  • Glucuronidase
  • Humans
  • Kidney Failure, Chronic
  • Kidney Tubules
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptor, Fibroblast Growth Factor, Type 2
  • Signal Transduction
  • Syndecan-1

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