Abstract
Tubulo-interstitial fibrosis has been recognized as the hallmark of progression of chronic kidney disease, but, despite intensive research studies, there are currently no biomarkers or effective treatments for this condition. In this context, a promising candidate could be heparanase-1 (HPSE), an endoglycosidase that cleaves heparan sulfate chains and thus takes part in extracellular matrix remodeling. As largely described, it has a central role in the pathogenesis of cancer and inflammation, and it participates in the complex biological machinery involved in the onset of different renal proteinuric diseases (e.g., diabetic nephropathy, glomerulonephritis). Additionally, HPSE may significantly influence the progression of chronic kidney damage trough its major role in the biological pathway of renal fibrogenesis. Here, we briefly summarize data supporting the role of HPSE in renal damage, focusing on recent evidences that demonstrate the capability of this enzyme to modulate the signaling of pro-fibrotic factors such as FGF-2 and TGF-β and consequently to control the epithelial-mesenchymal transition in renal tubular cells. We also emphasize the need of the research community to undertake studies and clinical trials to assess the potential clinical employment of this enzyme as diagnostic and prognostic tool and/or its role as therapeutic target for new pharmacological interventions.
Highlights
Background improvements in drug therapies over the years have significantly slowed the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), we still remain far from being able to prevent a sizable proportion of patients from need for dialysis or transplantation [1]
HPSE triggers a number of signaling pathways by: (1) digesting heparan sulfate (HS) chains and causing the release of growth factors and cytokines bound to HS, thereby regulating their free levels in the pericellular microenvironment; (2) interacting via its C-terminal domain [22], with several transmembrane heparanase-binding proteins (HBP) and activating kinases such as Src, Akt, and p38 MAPK; (3) modulating the activity of the fibroblast growth factor-2 (FGF-2) and transforming growth factor-β (TGF-β) signaling cascades [23, 24] and (4) converting the soluble HS fragments of SDC1 from inhibitors into potent activators of FGF-2 signaling [25]
Goldberg et al [38] have recently shown that HPSE fuels chronic inflammation in diabetic nephropathy: inactive HPSE produced by glomeruli and activated by cathepsinl released by tubular cells sustains a persistent activation of kidney-damaging macrophages, creating chronic inflammatory conditions and fostering macrophagemediated renal injury (Figure 4)
Summary
Improvements in drug therapies over the years have significantly slowed the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), we still remain far from being able to prevent a sizable proportion of patients from need for dialysis or transplantation [1]. Tubular epithelial-mesenchymal transdifferentiation (EMT) into myofibroblasts, is a process first identified in mice and, more recently, in humans, representing an important source of these cells in kidney, contributes to the onset of TIF (Figure 1: top) and to the progression of CKD [13].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
