title: Heparanase and syndecan-1 interplay orchestrates fibroblast growth factor-2-induced epithelial-mesenchymal transition in renal tubular cells.
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.
authors.affiliation: Department of Experimental Biomedical Sciences, University of Padova, 35122 Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Masola
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gastaldello
authors.forename: Angela
authors.initials: A
authors.lastname: D'Angelo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Onisto
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
mesh_terms: D019898:Autocrine Communication / Q000235:genetics; D002460:Cell Line; D004789:Enzyme Activation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051497:Receptor, Fibroblast Growth Factor, Type 2; D053668:Syndecan-1; D000099175:Heparanase; C508241:SDC1 protein, human
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