2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Levidiotis, V. Articles by Power, D. A. Search for Related Content PubMed PubMed Citation Articles by Levidiotis, V. Articles by Power, D. A.

Heparanase Is Involved in the Pathogenesis of Proteinuria as a Result of Glomerulonephritis

Vicki Levidiotis^*, Craig Freeman, Chris Tikellis, Mark E. Cooper and David A. Power^*

*Department of Nephrology, Austin Research Institute, and Department of Medicine, University of Melbourne, Austin & Repatriation Medical Center, Studley Road Heidelberg, Victoria, Australia; Division of Immunology and Genetics, Cancer and Vascular Biology Group, The John Curtin School of Medical Research, Australian National University, Canberra, Australia; and Baker Heart Research Institute, Alfred Hospital, Victoria, Australia

Correspondence to Dr. Vicki Levidiotis, Department of Nephrology, Austin & Repatriation Medical Center, "A" Block, Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 613-9496-5634; Fax: 613-9496-5123;

ABSTRACT. The -D-endoglycosidase heparanase has been proposed to be important in the pathogenesis of proteinuria by selectively degrading the negatively charged side chains of heparan sulfate proteoglycans within the glomerular basement membrane. A loss of negatively charged heparan sulfate proteoglycans may result in alteration of the permselective properties of the glomerular basement membrane, loss of glomerular epithelial and endothelial cell anchor points, and liberation of growth factors. In this study, therefore, the role of heparanase in passive Heymann nephritis (PHN) was examined. Normal glomeruli showed low-level heparanase expression as determined by immunohistochemistry and Western blot analysis. Days 5, 14, and 28 of PHN were associated with an increase in endothelial and glomerular epithelial cell heparanase. Reverse transcription–PCR confirmed a significant increase in mRNA at day 21 of disease (P < 0.0004). Furthermore, urinary and glomerular heparanase activities were significantly increased at days 5 and 21 of disease, respectively. Western blot analysis of isolated glomeruli separated into membrane- and cytosol-enriched protein fractions showed that the active 58-kD heparanase species was increased but restricted to the cytosol of diseased glomeruli at day 21. The inactive 65-kD precursor, however, was found in membrane and cytosol-diseased fractions, suggesting cell membrane processing. Complement depletion prevented glomerular heparanase expression; in addition, administration of a polyclonal anti-heparanase antibody significantly reduced urinary protein excretion at day 5 of disease to 62 ± 11 mg/d compared with 203 ± 43 and 159 ± 18 mg/d in the normal rabbit serum– and normal saline-treated experimental groups, respectively (P < 0.002). Proteinuria was reduced in the absence of any altered glomerular C5b-9 activity, sheep IgG deposition, or rat anti-sheep antibody titers. These data suggest that heparanase contributes to the pathogenesis of proteinuria in PHN. E-mail: Vicki.Levidiotis@austin.org.au

This article has been cited by other articles:

				R. J. Wood and M. D. Hulett Cell Surface-expressed Cation-independent Mannose 6-Phosphate Receptor (CD222) Binds Enzymatically Active Heparanase Independently of Mannose 6-Phosphate to Promote Extracellular Matrix Degradation J. Biol. Chem., February 15, 2008; 283(7): 4165 - 4176. [Abstract] [Full Text] [PDF]

				E. J. Lewis and X. Xu Abnormal Glomerular Permeability Characteristics in Diabetic Nephropathy: Implications for the therapeutic use of low-molecular weight heparin Diabetes Care, February 1, 2008; 31(Supplement_2): S202 - S207. [Abstract] [Full Text] [PDF]

				A. Singh, S. C. Satchell, C. R. Neal, E. A. McKenzie, J. E. Tooke, and P. W. Mathieson Glomerular Endothelial Glycocalyx Constitutes a Barrier to Protein Permeability J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2885 - 2893. [Abstract] [Full Text] [PDF]

				R. J.H. Smith, J. Alexander, P. N. Barlow, M. Botto, T. L. Cassavant, H. T. Cook, S. R. de Cordoba, G. S. Hageman, T. S. Jokiranta, W. J. Kimberling, et al. New Approaches to the Treatment of Dense Deposit Disease J. Am. Soc. Nephrol., September 1, 2007; 18(9): 2447 - 2456. [Abstract] [Full Text] [PDF]

				T. J.M. Wijnhoven, J. F.M. Lensen, R. G.P. Wismans, M. Lamrani, L. A.H. Monnens, R. A. Wevers, A. L.W.M.M. Rops, J. van der Vlag, J. H.M. Berden, L. P.W.J. van den Heuvel, et al. In Vivo Degradation of Heparan Sulfates in the Glomerular Basement Membrane Does Not Result in Proteinuria J. Am. Soc. Nephrol., March 1, 2007; 18(3): 823 - 832. [Abstract] [Full Text] [PDF]

				S. J. Harvey and J. H. Miner Breaking Down the Barrier: Evidence against a Role for Heparan Sulfate in Glomerular Permselectivity J. Am. Soc. Nephrol., March 1, 2007; 18(3): 672 - 674. [Full Text] [PDF]

				A. Kramer, M. van den Hoven, A. Rops, T. Wijnhoven, L. van den Heuvel, J. Lensen, T. van Kuppevelt, H. van Goor, J. van der Vlag, G. Navis, et al. Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2513 - 2520. [Abstract] [Full Text] [PDF]

				A. V. Cybulsky, R. J. Quigg, and D. J. Salant Experimental membranous nephropathy redux Am J Physiol Renal Physiol, October 1, 2005; 289(4): F660 - F671. [Abstract] [Full Text] [PDF]

				J. B. Maxhimer, M. Somenek, G. Rao, C. E. Pesce, D. Baldwin Jr., P. Gattuso, M. M. Schwartz, E. J. Lewis, R. A. Prinz, and X. Xu Heparanase-1 Gene Expression and Regulation by High Glucose in Renal Epithelial Cells: A Potential Role in the Pathogenesis of Proteinuria in Diabetic Patients Diabetes, July 1, 2005; 54(7): 2172 - 2178. [Abstract] [Full Text] [PDF]

				F. Levy-Adam, G. Abboud-Jarrous, M. Guerrini, D. Beccati, I. Vlodavsky, and N. Ilan Identification and Characterization of Heparin/Heparan Sulfate Binding Domains of the Endoglycosidase Heparanase J. Biol. Chem., May 27, 2005; 280(21): 20457 - 20466. [Abstract] [Full Text] [PDF]

				V. Levidiotis, C. Freeman, M. Punler, P. Martinello, B. Creese, V. Ferro, J. van der Vlag, J. H.M. Berden, C. R. Parish, and D. A. Power A Synthetic Heparanase Inhibitor Reduces Proteinuria in Passive Heymann Nephritis J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2882 - 2892. [Abstract] [Full Text] [PDF]

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