title: Nephroprotective effect of heparanase in experimental nephrotic syndrome.
abstract: BACKGROUND
  Heparanase, an endoglycosidase that cleaves heparan sulfate (HS), is involved in various biologic processes. Recently, an association between heparanase and glomerular injury was suggested. The present study examines the involvement of heparanase in the pathogenesis of Adriamycin-induced nephrotic syndrome (ADR-NS) in a mouse model.
  
  
  METHODS
  BALB/c wild-type (wt) mice and heparanase overexpressing transgenic mice (hpa-TG) were tail-vein injected with either Adriamycin (ADR, 10 mg/kg) or vehicle. Albuminuria was investigated at days 0, 7, and 14 thereafter. Mice were sacrificed at day 15, and kidneys were harvested for various analyses: structure and ultrastructure alterations, podocyte proteins expression, and heparanase enzymatic activity.
  
  
  RESULTS
  ADR-injected wt mice developed severe albuminuria, while ADR-hpa-TG mice showed only a mild elevation in urinary albumin excretion. In parallel, light microscopy of stained cross sections of kidneys from ADR-injected wt mice, but not hpa-TG mice, showed mild to severe glomerular and tubular damage. Western blot and immunofluorescence analyses revealed significant reduction in nephrin and podocin protein expression in ADR-wt mice, but not in ADR-hpa-TG mice. These results were substantiated by electron-microscopy findings showing massive foot process effacement in injected ADR-wt mice, in contrast to largely preserved integrity of podocyte architecture in ADR-hpa-TG mice.
  
  
  CONCLUSIONS
  Our results suggest that heparanase may play a nephroprotective role in ADR-NS, most likely independently of HS degradation. Moreover, hpa-TG mice comprise an invaluable in vivo platform to investigate the interplay between heparanase and glomerular injury.
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Suheir
authors.initials: S
authors.lastname: Assady
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Joel
authors.initials: J
authors.lastname: Alter
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Axelman
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Zohar
authors.affiliation: Department of Pathology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Edmond
authors.initials: E
authors.lastname: Sabo
authors.affiliation: Department of Nephrology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Litvak
authors.affiliation: Clinical Laboratories Division, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Marielle
authors.initials: M
authors.lastname: Kaplan
authors.affiliation: Cancer and Vascular Biology Research Centre, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
authors.affiliation: Cancer and Vascular Biology Research Centre, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.affiliation: Research Unit, Rambam Health Care Campus, Haifa, Israel; Department of Physiology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Zaid
authors.initials: Z
authors.lastname: Abassi
mesh_terms: D000419:Albuminuria; D000818:Animals; D015153:Blotting, Western; D004317:Doxorubicin / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006652:Histological Techniques; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009404:Nephrotic Syndrome / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D000099175:Heparanase
chemical_list: D004317:Doxorubicin; D005966:Glucuronidase; D000099175:Heparanase