title: Heparanase: A Potential New Factor Involved in the Renal Epithelial Mesenchymal Transition (EMT) Induced by Ischemia/Reperfusion (I/R) Injury.
abstract: Ischemia/reperfusion (I/R) is an important cause of acute renal failure and delayed graft function, and it may induce chronic renal damage by activating epithelial to mesenchymal transition (EMT) of renal tubular cells. Heparanase (HPSE), an endoglycosidase that regulates FGF-2 and TGFβ-induced EMT, may have an important role. Therefore, aim of this study was to evaluate its role in the I/R-induced renal pro-fibrotic machinery by employing in vitro and in vivo models.
  
  
  
  Wild type (WT) and HPSE-silenced renal tubular cells were subjected to hypoxia and reoxygenation in the presence or absence of SST0001, an inhibitor of HPSE. In vivo, I/R injury was induced by bilateral clamping of renal arteries for 30 min in transgenic mice over-expressing HPSE (HPA-tg) and in their WT littermates. Mice were sacrificed 48 and 72 h after I/R. Gene and protein EMT markers (α-SMA, VIM and FN) were evaluated by bio-molecular and histological methodologies.
  
  
  
  In vitro: hypoxia/reoxygenation (H/R) significantly increased the expression of EMT-markers in WT, but not in HPSE-silenced tubular cells. Notably, EMT was prevented in WT cells by SST0001 treatment. In vivo: I/R induced a remarkable up-regulation of EMT markers in HPA-tg mice after 48-72 h. Noteworthy, these effects were absent in WT animals.
  
  
  
  In conclusion, our results add new insights towards understanding the renal biological mechanisms activated by I/R and they demonstrate, for the first time, that HPSE is a pivotal factor involved in the onset and development of I/R-induced EMT. It is plausible that in future the inhibition of this endoglycosidase may represent a new therapeutic approach to minimize/prevent fibrosis and slow down chronic renal disease progression in native and transplanted kidneys.
authors.affiliation: Renal Unit, Department of Medicine, Verona, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Masola
authors.affiliation: Renal Unit, Department of Medicine, Verona, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.affiliation: Renal Unit, Columbus-Gemelli Hospital, Catholic University of the Sacred Heart, Roma, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.affiliation: University of Padova, Department of Biomedical Sciences Padova, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Onisto
authors.affiliation: Renal Unit, Department of Medicine, Verona, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bellin
authors.affiliation: Renal Unit, Columbus-Gemelli Hospital, Catholic University of the Sacred Heart, Roma, Italy.
authors.forename: Gisella
authors.initials: G
authors.lastname: Vischini
authors.affiliation: Gastroenterology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Iyad
authors.initials: I
authors.lastname: Khamaysi
authors.affiliation: Internal Medicine A, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hassan
authors.affiliation: Internal Medicine E, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Shadi
authors.initials: S
authors.lastname: Hamoud
authors.affiliation: Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Omri
authors.initials: O
authors.lastname: Nativ
authors.affiliation: Department of Internal Medicine, Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Samuel
authors.initials: SN
authors.lastname: Heyman
authors.affiliation: Renal Unit, Department of Medicine, Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.affiliation: Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Physiology and Biophysics, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Research Unit, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
mesh_terms: D000818:Animals; D002460:Cell Line; D058750:Epithelial-Mesenchymal Transition; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000503:physiopathology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015427:Reperfusion Injury / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D000099175:Heparanase