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Induction of Glomerular Heparanase Expression in Rats with Adriamycin Nephropathy Is Regulated by Reactive Oxygen Species and the Renin-Angiotensin System

Andrea Kramer^*,, Mabel van den Hoven^,, Angelique Rops^,, Tessa Wijnhoven^||,¶, Lambert van den Heuvel^¶, Joost Lensen^||, Toin van Kuppevelt^||, Harry van Goor^*, Johan van der Vlag^,, Gerjan Navis^* and Jo H.M. Berden^,

Departments of ^* Pathology and Nephrology, University Medical Center Groningen, Nephrology Research Laboratory and ^|| Department of Matrix Biochemistry, Nijmegen Centre for Molecular Life Sciences, and Division of Nephrology and ^¶ Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Address correspondence to: Dr. Jo H.M. Berden, Division of Nephrology (464), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Phone: +31-24-3614761; Fax: +31-24-3540022; E-mail: j.berden{at}nier.umcn.nl

Received for publication February 28, 2006. Accepted for publication June 29, 2006.

Heparan sulfate (HS) in the glomerular basement membrane (GBM) is important for regulation of the charge-dependent permeability. Heparanase has been implicated in HS degradation in several proteinuric diseases. This study analyzed the role of heparanase in HS degradation in Adriamycin nephropathy (AN), a model of chronic proteinuria-induced renal damage. Expression of heparanase, HS, and the core protein of agrin (to which HS is attached) was determined on kidney sections from rats with AN in different experiments. First, expression was examined in a model of unilateral AN in a time-course study at 6-wk intervals until week 30. Second, rats were treated with the hydroxyl radical scavenger dimethylthiourea (DMTU) during bilateral AN induction. Finally, 6 wk after AN induction, rats were treated with angiotensin II receptor type 1 antagonist (AT1A) or vehicle for 2 wk. Heparanase expression was increased in glomeruli of rats with AN, which correlated with HS reduction at all time points and in all experiments. Treatment with DMTU prevented the increased heparanase expression, the loss of GBM HS, and reduced albuminuria. Finally, treatment of established proteinuria with AT1A significantly reduced heparanase expression and restored glomerular HS. In conclusion, an association between heparanase expression and reduction of glomerular HS in AN was observed. The effects of DMTU suggest a role for reactive oxygen species in upregulation of heparanase. Antiproteinuric treatment by AT1A decreased heparanase expression and restored HS expression. These results suggest involvement of radicals and angiotensin II in the modulation of GBM permeability through HS and heparanase expression.

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