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J. Biol. Chem., Vol. 281, Issue 40, 29606-29613, October 6, 2006

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No Change in Glomerular Heparan Sulfate Structure in Early Human and Experimental Diabetic Nephropathy^*

Jacob van den Born¹, Brenda Pisa, Marinka A. H. Bakker, Johanna W. A. M. Celie, Carin Straatman, Steven Thomas^¶, Gian C. Viberti^¶, Lena Kjellen^||, and Jo H. M. Berden

From the Department of Nephrology, Radboud University Medical Center Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands, the Department of Molecular Cell Biology and Immunology, VU University Medical Center, P. O. Box 7057, 1007 MB Amsterdam, The Netherlands, the ^¶Department of Diabetes, Endocrinology, and Internal Medicine, Guy's Hospital, St. Thomas Street, London SE1 9RT, United Kingdom, and the ^||Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23, Uppsala, Sweden

Heparan sulfate (HS) proteoglycans are major anionic glycoconjugates of the glomerular basement membrane and are thought to contribute to the permeability properties of the glomerular capillary wall. In this study we evaluated whether the development of (micro) albuminuria in early human and experimental diabetic nephropathy is related to changes in glomerular HS expression or structure. Using a panel of recently characterized antibodies, glomerular HS expression was studied in kidney biopsies of type I diabetic patients with microalbuminuria or early albuminuria and in rat renal tissue after 5 months diabetes duration. Glomerular staining, however, revealed no differences between control and diabetic specimens. A significant (p < 0.05) 60% increase was found in HS N-deacetylase activity, a key enzyme in HS sulfation reactions, in diabetic glomeruli. Structural analysis of glomerular HS after in vivo and in vitro radiolabeling techniques revealed no changes in HS N-sulfation or charge density. Also HS chain length, protein binding properties, as well as disaccharide composition did not differ between control and diabetic glomerular HS samples. These results indicate that in experimental and early human diabetic nephropathy, increased urinary albumin excretion is not caused by loss of glomerular HS expression or sulfation and suggest other mechanisms to be responsible for increased glomerular albumin permeability.

Received for publication, February 17, 2006 , and in revised form, July 13, 2006.

^* This work was supported by a grant from the Dutch Diabetes Foundation (DFN 940-10-009). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Cell Biology and Immunology VU University Medical Center, P. O. Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: 31-20-444-8078; Fax: 31-20-444-8081; E-mail: j.vandenborn{at}vumc.nl.

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