A new mechanism of action of sulodexide in diabetic nephropathy: inhibits heparanase-1 and prevents FIG-2-induced renal epithelial-mesenchymal transition

Giovanni Gambaro, Valentina Masola, Maurizio Onisto, Gianluigi Zaza, Antonio Lupo

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

49 Citazioni (Scopus)

Abstract

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 buy an ELISA assay. We and 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 mug/ml. In FGF-2 treated tubular cells, Sulodexide also prevents the over-expression of the mesenchymal markers alphaSMA, 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.
Lingua originaleEnglish
pagine (da-a)213-213
Numero di pagine16
RivistaJournal of Translational Medicine
Volume10
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • glycosaminoglycans

Fingerprint

Entra nei temi di ricerca di 'A new mechanism of action of sulodexide in diabetic nephropathy: inhibits heparanase-1 and prevents FIG-2-induced renal epithelial-mesenchymal transition'. Insieme formano una fingerprint unica.

Cita questo