Heparanase and Renal Fibrosis

Abstract

The multiple drug therapy has led, over the years, a significant slowing of the chronic kidney disease progression towards end stage renal disease, but we are still far from the development of therapeutic interventions able to stop this mechanism. Clinical-pathological studies have clearly shown that fibrosis is the main process involved in chronic renal damage and that pathogenic mechanism underlying this condition arises in the tubular compartment. In particular, the epithelial-mesenchymal transition (EMT) plays an important role in the development of chronic damage. During EMT, the tubular epithelial cells acquire mesenchymal properties, undergo cytoskeleton remodeling and basement membrane degradation. Then they are able to migrate into interstitium where they play a key role in the fibrosis. In this context, seems to play a central role the enzyme heparanase (HPSE), an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) side chains at a limited number of sites, hence participates in extracellular matrix (ECM) degradation and remodeling. The degradation of several constituents of the ECM, including heparan sulfate proteoglycans (HSPG), promotes the release of growth factors such as Fibroblast growth factor-2 (FGF-2) that induces the expression of mesenchymal markers alpha-SMA, Vimentin (VIM) and fibronectin (FN), leads to degradation of the basement membrane by means of the secretion of matrix metalloproteinases (MMPs) and increases the cell motility. The heparanase expression is finely regulated by transcription factor, DNA methylation and various endogenous molecules. In vivo studies have shown its overexpression in histological sections of biopsies performed in patients with chronic kidney disease (e.g. diabetic nephropathy). Therefore, given the important role of this enzyme clinicians and researcher are developing several strategies to inhibit its gene expression and/or its enzymatic activity. Finally, it has been proposed its possible use as a biomarker of progression of tubulointerstitial damage for routinely use in clinical nephrology.