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Open Access Research

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

Valentina Masola1, Maurizio Onisto1, Gianluigi Zaza2, Antonio Lupo2 and Giovanni Gambaro3*

Author Affiliations

1 Department of Biomedical Sciences, University of Padova, Padova, Italy

2 Department of Medicine, Section of Nephrology, University of Verona, Verona, Italy

3 Division of Nephrology and Dialysis, Institute of Internal Medicine and Medical Specialties, Columbus-Gemelli University Hospital, Renal Program, Catholic University, Via Moscati, 31., Rome, 00168, Italy

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Journal of Translational Medicine 2012, 10:213  doi:10.1186/1479-5876-10-213

Published: 24 October 2012

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:
Diabetic nephropathy; Epithelial-mesenchymal transition; Fibrosis; Heparanase-1; Sulodexide; Tubular cells