title: Heparanase is a key player in renal fibrosis by regulating TGF-β expression and activity.
abstract: Epithelial-mesenchymal transition (EMT) of tubular cells is one of the mechanisms which contribute to renal fibrosis and transforming growth factor-β (TGF-β) is one of the main triggers. Heparanase (HPSE) is an endo-β-D-glucuronidase that cleaves heparan-sulfate thus regulating the bioavailability of growth factors (FGF-2, TGF-β). HPSE controls FGF-2-induced EMT in tubular cells and is necessary for the development of diabetic nephropathy in mice. The aim of this study was to investigate whether HPSE can modulate the expression and the effects of TGF-β in tubular cells. First we proved that the lack of HPSE or its inhibition prevents the increased synthesis of TGF-β by tubular cells in response to pro-fibrotic stimuli such as FGF-2, advanced glycosylation end products (AGE) and albumin overload. Second, since TGF-β may derive from sources different from tubular cells, we investigated whether HPSE modulates tubular cell response to exogenous TGF-β. HPSE does not prevent EMT induced by TGF-β although it slows its onset; indeed in HPSE-silenced cells the acquisition of a mesenchymal phenotype does not develop as quickly as in wt cells. Additionally, TGF-β induces an autocrine loop to sustain its signal, whereas the lack of HPSE partially interferes with this autocrine loop. Overall these data confirm that HPSE is a key player in renal fibrosis since it interacts with the regulation and the effects of TGF-β. HPSE is needed for pathological TGF-β overexpression in response to pro-fibrotic factors. Furthermore, HPSE modulates TGF-β-induced EMT: the lack of HPSE delays tubular cell transdifferentiation, and impairs the TGF-β autocrine loop.
authors.affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Italy; Department of Biomedical Sciences, University of Padova, Italy. Electronic address: valentina.masola@unipd.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Masola
authors.affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Italy. Electronic address: gianluigi.zaza@univr.it.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.affiliation: Department of Biomedical Sciences, University of Padova, Italy. Electronic address: mfrancesca.secchi@libero.it.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Secchi
authors.affiliation: Division of Nephrology and Dialysis, Columbus-Gemelli Hospital, Catholic University, School of Medicine, Rome, Italy. Electronic address: giovanni.gambaro@rm.unicatt.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.affiliation: Renal Unit, Department of Medicine, University-Hospital of Verona, Italy. Electronic address: antonio.lupo@univr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.affiliation: Department of Biomedical Sciences, University of Padova, Italy. Electronic address: maurizio.onisto@unipd.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Onisto
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000099175:Heparanase
chemical_list: D000199:Actins; D015415:Biomarkers; D005353:Fibronectins; D005966:Glucuronidase; D020780:Matrix Metalloproteinase 9; D016212:Transforming Growth Factor beta; D014746:Vimentin; D000099175:Heparanase; C541116:ACTA2 protein, human
keywords: Epithelial–mesenchymal transition; Heparanase; Renal fibrosis; TGF-β