Involvement of heparanase in the pathogenesis of acute kidney injury: nephroprotective effect of PG545

// Zaid Abassi 1,2 , Shadi Hamoud 3 , Ahmad Hassan 4 , Iyad Khamaysi 5 , Omri Nativ 1 , Samuel N. Heyman 6 , Rabia Shekh Muhammad 3 , Neta Ilan 7 , Preeti Singh 7 , Edward Hammond 8 , Gianluigi Zaza 9 , Antonio Lupo 9 , Maurizio Onisto 10 , Gloria Bellin 9 , Valentina Masola 9 , Israel Vlodavsky 7 and Giovani Gambaro 11 1 Department of Physiology, The Rappaport Faculty of Medicine, Technion, Haifa, Israel 2 Department of Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel 3 Department of Internal Medicine E, Rambam Health Care Campus, Haifa, Israel 4 Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel 5 Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel 6 Department of Internal Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel 7 Department of Cancer and Vascular Biology Research Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel 8 Zucero Therapeutics, Brisbane, Queensland, Australia 9 Department of Medicine, Renal Unit, Verona, Italy 10 Department of Biomedical Sciences, University of Padova, Catholic University of the Sacred Heart, Roma, Italy 11 Department of Medicine, Columbus-Gemelli Hospital, Catholic University of the Sacred Heart, Roma, Italy Correspondence to: Zaid Abassi, email: // Israel Vlodavsky, email: // Keywords : acute kidney injury, heparanase, ischemia, inflammation, PG545 Received : February 09, 2017 Accepted : March 16, 2017 Published : March 25, 2017 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.