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- Title
A new mechanism of action of sulodexide in diabetic nephropathy: inhibits heparanase-1 and prevents FGF-2-induced renal epithelial-mesenchymal transition.
- Authors
Masola, Valentina; Onisto, Maurizio; Zaza, Gianluigi; Lupo, Antonio; Gambaro, Giovanni
- 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 ɑSMA, 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.
- Subjects
DIABETIC nephropathies; HEPARANASE; GLYCOSAMINOGLYCANS; ENDOGLYCOSIDASES; HEPARAN sulfate; GENE expression; PREVENTION of disease progression; THERAPEUTICS
- Publication
Journal of Translational Medicine, 2012, Vol 10, Issue 1, p1
- ISSN
1479-5876
- Publication type
Article
- DOI
10.1186/1479-5876-10-213