A synthetic heparanase inhibitor reduces proteinuria in passive heymann nephritis

Levidiotis, V., Freeman, C., Punler, M., Martinello, P., Creese, B., Ferro, V., van der Vlag, J., Berden, Jo H.M., Parish, C.R. and Power, D.A. (2004) A synthetic heparanase inhibitor reduces proteinuria in passive heymann nephritis. Journal of the American Society of Nephrology, 15 11: 2882-2892. doi:10.1097/01.ASN.0000142426.55612.6D

Author Levidiotis, V.
Freeman, C.
Punler, M.
Martinello, P.
Creese, B.
Ferro, V.
van der Vlag, J.
Berden, Jo H.M.
Parish, C.R.
Power, D.A.
Title A synthetic heparanase inhibitor reduces proteinuria in passive heymann nephritis
Journal name Journal of the American Society of Nephrology   Check publisher's open access policy
ISSN 1046-6673
Publication date 2004-11
Sub-type Article (original research)
DOI 10.1097/01.ASN.0000142426.55612.6D
Volume 15
Issue 11
Start page 2882
End page 2892
Total pages 11
Editor Bonnie O'Brien
Place of publication Washington, D.C., U.S.A.
Publisher American Society of Nephrology
Language eng
Subject 1103 Clinical Sciences
Formatted abstract
The β-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.
© 2004 American Society of Nephrology.

Keyword Heymann nephritis
Heparanase inhibitor
Renal function
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 38 times in Thomson Reuters Web of Science Article | Citations
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