title: A new mechanism of action of sulodexide in diabetic nephropathy: inhibits heparanase-1 and prevents FGF-2-induced renal epithelial-mesenchymal transition.
abstract: BACKGROUND
  Epithelial-mesenchymal transition of tubular cells is a widely recognized mechanism that sustains interstitial fibrosis in diabetic nephropathy (DN). The signaling of FGF-2, a growth factor involved in this mechanism, is regulated by glycosaminoglycans. Heparanase-1, an endoglycosidase that cleaves heparan sulfate, is implicated in the pathogenesis of diabetic nephropathy and is necessary to FGF-2 for the induction of tubular cells transition. Well known Heparanase-1 inhibitors are heparin(s) and sulodexide, a low-molecular weight heparin - dermatan sulphate blend, which is effective in the treatment of DN.
  
  
  METHODS
  We have investigated the inhibition by sulodexide and its components of Heparanase-1 by an ELISA assay. We have analyzed its effect on the epithelial-mesenchymal transition of tubular cells by real time gene expression analysis, zymography and migration assay.
  
  
  RESULTS
  Results show that sulodexide is an effective heparanase-1 inhibitor, exclusively in virtue to the heparin component, with an IC50 of 5 μg/ml. In FGF-2 treated tubular cells, sulodexide also prevents the over-expression of the mesenchymal markers αSMA, vimentin and fibronectin and the motility increase, i.e. the epithelial-mesenchymal transition of tubular cells. Moreover, sulodexide prevents FGF-2 induced heparanase-1 and MMP9 increase switching off the autocrine loop that FGF-2 activates to support its signal.
  
  
  CONCLUSIONS
  The findings highlight the capacity of sulodexide to inhibit heparanase-1 and to control tubular fibrosis triggered by epithelial-mesenchymal transition. In conclusion, these sulodexide activities support the value of this agent in controlling the progression of nephropathy to renal failure.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Padova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Masola
authors.forename: Maurizio
authors.initials: M
authors.lastname: Onisto
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006025:Glycosaminoglycans / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism; D000099175:Heparanase
chemical_list: D015415:Biomarkers; D016222:Fibroblast Growth Factor 2; D005966:Glucuronidase; D006025:Glycosaminoglycans; D020780:Matrix Metalloproteinase 9; D053668:Syndecan-1; D000099175:Heparanase; C508241:SDC1 protein, human; C007858:glucuronyl glucosamine glycan sulfate