title: Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545.
abstract: Despite the high prevalence of acute kidney injury (AKI) and its association with increased morbidity and mortality, therapeutic approaches for AKI are disappointing. This is largely attributed to poor understanding of the pathogenesis of AKI. Heparanase, an endoglycosidase that cleaves heparan sulfate, is involved in extracellular matrix turnover, inflammation, kidney dysfunction, diabetes, fibrosis, angiogenesis and cancer progression. The current study examined the involvement of heparanase in the pathogenesis of ischemic reperfusion (I/R) AKI in a mouse model and the protective effect of PG545, a potent heparanase inhibitor. I/R induced tubular damage and elevation in serum creatinine and blood urea nitrogen to a higher extent in heparanase over-expressing transgenic mice vs. wild type mice. Moreover, TGF-β, vimentin, fibronectin and α-smooth muscle actin, biomarkers of fibrosis, and TNFα, IL6 and endothelin-1, biomarkers of inflammation, were upregulated in I/R induced AKI, primarily in heparanase transgenic mice, suggesting an adverse role of heparanase in the pathogenesis of AKI. Remarkably, pretreatment of mice with PG545 abolished kidney dysfunction and the up-regulation of heparanase, pro-inflammatory (i.e., IL-6) and pro-fibrotic (i.e., TGF-β) genes induced by I/R. The present study provides new insights into the involvement of heparanase in the pathogenesis of ischemic AKI.Our results demonstrate that heparanase plays a deleterious role in the development of renal injury and kidney dysfunction,attesting heparanase inhibition as a promising therapeutic approach for AKI.
authors.affiliation: Department of Physiology, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.|Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
authors.affiliation: Department of Internal Medicine E, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Shadi
authors.initials: S
authors.lastname: Hamoud
authors.affiliation: Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hassan
authors.affiliation: Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Iyad
authors.initials: I
authors.lastname: Khamaysi
authors.affiliation: Department of Physiology, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Omri
authors.initials: O
authors.lastname: Nativ
authors.affiliation: Department of Internal Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Heyman
authors.affiliation: Department of Internal Medicine E, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Rabia Shekh
authors.initials: RS
authors.lastname: Muhammad
authors.affiliation: Department of Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Department of Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singh
authors.affiliation: Zucero Therapeutics, Brisbane, Queensland, Australia.
authors.forename: Edward
authors.initials: E
authors.lastname: Hammond
authors.affiliation: Department of Medicine, Renal Unit, Verona, Italy.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Zaza
authors.affiliation: Department of Medicine, Renal Unit, Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.affiliation: Department of Biomedical Sciences, University of Padova, Catholic University of the Sacred Heart, Roma, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Onisto
authors.affiliation: Department of Medicine, Renal Unit, Verona, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bellin
authors.affiliation: Department of Medicine, Renal Unit, Verona, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Masola
authors.affiliation: Department of Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Department of Medicine, Columbus-Gemelli Hospital, Catholic University of the Sacred Heart, Roma, Italy.
authors.forename: Giovani
authors.initials: G
authors.lastname: Gambaro
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D015427:Reperfusion Injury / Q000473:pathology; D012503:Saponins / Q000494:pharmacology / Q000627:therapeutic use; D015854:Up-Regulation; D000099175:Heparanase
chemical_list: D015415:Biomarkers; D005966:Glucuronidase; D012503:Saponins; D000099175:Heparanase; C557899:PG 545
keywords: PG545; acute kidney injury; heparanase; inflammation; ischemia