A new mechanism of action of sulodexide in diabetic nephropathy: inhibits heparanase-1 and prevents FGF-2-induced renal epithelial-mesenchymal transition
Open Access
- 24 October 2012
- journal article
- Published by Springer Science and Business Media LLC in Journal of Translational Medicine
- Vol. 10 (1), 213
- https://doi.org/10.1186/1479-5876-10-213
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.Keywords
This publication has 28 references indexed in Scilit:
- Heparanase and Syndecan-1 Interplay Orchestrates Fibroblast Growth Factor-2-induced Epithelial-Mesenchymal Transition in Renal Tubular CellsJournal of Biological Chemistry, 2012
- Heparanase Is Essential for the Development of Diabetic Nephropathy in MiceDiabetes, 2011
- New Insights into Epithelial-Mesenchymal Transition in Kidney FibrosisJournal of the American Society of Nephrology, 2010
- Heparanase activity in alveolar and embryonal rhabdomyosarcoma: implications for tumor invasionBMC Cancer, 2009
- EMT and proteinuria as progression factorsKidney International, 2009
- In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitroNature Protocols, 2007
- The Role of Sulodexide in the Treatment of Diabetic NephropathyDrugs, 2007
- Increased expression of heparanase in overt diabetic nephropathyKidney International, 2006
- Sulodexide: A Renewed Interest in This GlycosaminoglycanCardiovascular Drug Reviews, 2006
- Reactive Oxygen Species and Matrix Remodeling in Diabetic KidneyJournal of the American Society of Nephrology, 2003