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A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis

Vicki Levidiotis^*,, Craig Freeman, Malcolm Punler^¶, Paul Martinello, Brian Creese^||, Vito Ferro^||, Johan van der Vlag^#, Jo H.M. Berden^#, Christopher R. Parish and David A. Power^*,

*The Austin Research Institute, Department of Nephrology, and Department of Pathology and the University of Melbourne, Department of Medicine, Austin Health, Victoria, Australia; Cancer and Vascular Biology Group, Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, Australia; ^||Progen Industries Limited, Queensland, Australia; ^¶Inveresk Research, Tranent, Scotland; and ^#Division of Nephrology Nijmegen Centre for Molecular Life Sciences, University Medical Centre, Nijmegen, The Netherlands

Correspondence to Dr. V. Levidiotis, Department of Nephrology, Austin Health, "A" Block, Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 613-9496-5634; Fax: 613-9496-5123; E-mail: Vicki.Levidiotis{at}austin.org.au

The -D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by acting to selectively degrade the negatively charged side chains of heparan sulfate proteoglycans (HSPG) within the glomerular basement membrane (GBM). A loss of the negatively charged HSPG may result in alteration of the permselective properties of the GBM, loss of glomerular epithelial and endothelial cell anchor points, and liberation of growth factors. This study examined the effect of PI-88, a sulfated oligosaccharide heparanase inhibitor, on renal function, glomerular ultrastructure, and proteinuria. Continuous PI-88 infusion at 25 mg/kg per d did not adversely affect animal behavior, growth, or GFR. Cortical tubular vacuolation, however, was observed by light microscopy, and GBM thickness was significantly reduced in these animals (P < 0.0002). Tissue distribution studies using [³⁵S]-labeled PI-88 revealed high levels of radioactivity in the kidney after a single subcutaneous injection of 25 mg/kg, suggesting protracted accumulation; moreover, active PI-88 was detected in urine. In passive Heymann nephritis, PI-88 delivered as a continuous infusion at 25 mg/kg per d significantly reduced autologous-phase proteinuria, at day 14 (P < 0.009), in the absence of altered sheep antibody deposition, C5b-9 deposition, and circulating rat anti-sheep antibody titers. Glomerular vascular endothelial growth factor and fibroblast growth factor expression was unaffected by PI-88 administration. However, PI-88 administration significantly prevented glomerular HSPG loss as demonstrated by quantitative immunofluorescence studies (P < 0.0001) in the absence of altered agrin distribution. These data therefore confirm the importance of heparanase in the development of proteinuria.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673