The multiple drug therapy has led, over the years, a significant slowing of the chronic kidney disease progressiontowards end stage renal disease, but we are still far from the development of therapeutic interventions able to stop thismechanism. Clinical-pathological studies have clearly shown that fibrosis is the main process involved in chronic renaldamage and that pathogenic mechanism underlying this condition arises in the tubular compartment. In particular, theepithelial-mesenchymal transition (EMT) plays an important role in the development of chronic damage. During EMT, thetubular 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, seemsto play a central role the enzyme heparanase (HPSE), an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) sidechains at a limited number of sites, hence participates in extracellular matrix (ECM) degradation and remodeling. Thedegradation of several constituents of the ECM, including heparan sulfate proteoglycans (HSPG), promotes the releaseof 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 secretionof matrix metalloproteinases (MMPs) and increases the cell motility. The heparanase expression is finely regulated bytranscription factor, DNA methylation and various endogenous molecules. In vivo studies have shown its overexpressionin 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 geneexpression and/or its enzymatic activity. Finally, it has been proposed its possible use as a biomarker of progression oftubulointerstitial damage for routinely use in clinical nephrology.
Eparanasi: un nuovo biomarker di fibrosi e un potenziale target farmacologico per ridurre la progressione del danno renale cronico
Zaza, Gianluigi
2012-01-01
Abstract
The multiple drug therapy has led, over the years, a significant slowing of the chronic kidney disease progressiontowards end stage renal disease, but we are still far from the development of therapeutic interventions able to stop thismechanism. Clinical-pathological studies have clearly shown that fibrosis is the main process involved in chronic renaldamage and that pathogenic mechanism underlying this condition arises in the tubular compartment. In particular, theepithelial-mesenchymal transition (EMT) plays an important role in the development of chronic damage. During EMT, thetubular 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, seemsto play a central role the enzyme heparanase (HPSE), an endo-β-D-glucuronidase that cleaves heparan sulfate (HS) sidechains at a limited number of sites, hence participates in extracellular matrix (ECM) degradation and remodeling. Thedegradation of several constituents of the ECM, including heparan sulfate proteoglycans (HSPG), promotes the releaseof 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 secretionof matrix metalloproteinases (MMPs) and increases the cell motility. The heparanase expression is finely regulated bytranscription factor, DNA methylation and various endogenous molecules. In vivo studies have shown its overexpressionin 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 geneexpression and/or its enzymatic activity. Finally, it has been proposed its possible use as a biomarker of progression oftubulointerstitial damage for routinely use in clinical nephrology.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
