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Protection of Endothelial Cells by Dextran Sulfate in Rats with Thrombotic Microangiopathy

Nobuaki Eto^*, Ichiro Kojima^*, Noriko Uesugi, Reiko Inagi, Toshio Miyata, Toshiro Fujita^*, Richard J. Johnson, Stuart J. Shankland^|| and Masaomi Nangaku^*

^* Division of Nephrology and Endocrinology, University of Tokyo, School of Medicine, Tokyo, Japan; Department of Pathology, Fukuoka University, School of Medicine, Fukuoka, Japan; Molecular and Cellular Nephrology, Institute of Medical Sciences, Tokai University, Kanagawa, Japan; Division of Nephrology, Hypertension, and Transplantation, University of Florida, Gainesville, Florida; and ^|| Division of Nephrology, University of Washington, Seattle, Washington

Address correspondence to: Dr. Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo, School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan. Phone: 81-3-5800-8648; Fax: 81-3-5800-8806; E-mail: mnangaku-tky{at}umin.ac.jp

Received for publication February 4, 2005. Accepted for publication July 4, 2005.

The characteristic features of thrombotic microangiopathy (TMA) include glomerular and peritubular capillary endothelial cell injury in association with loss of heparan sulfate proteoglycans on the cell surface and thrombus formation, followed by subsequent ischemic tubulointerstitial damage. It therefore was hypothesized that dextran sulfate (DXS) may protect the kidney against endothelial damage in a model of TMA. TMA was induced in rats by renal artery perfusion of an antiglomerular endothelial antibody, followed by the administration of DXS or vehicle. Renal damage was assessed by histologic analysis and measurements of blood urea nitrogen and creatinine. Whereas control rats developed severe renal failure with extensive glomerular and tubular injury, administration of DXS significantly protected renal function and preserved the glomerular endothelium and peritubular capillaries. The beneficial effect of DXS could be attributed to the ability of DXS to protect endothelial cells from coagulation and complement activation, as demonstrated by the histologic analysis. In addition, binding of the administered DXS to the surface of the glomerular endothelium was confirmed in TMA rats, suggesting that DXS acts as a "repair coat" of injured glomerular endothelium. In conclusion, DXS protects the kidney from experimental TMA. This protection may be mediated by DXS’s binding directly to the surface of glomerular endothelium and amelioration of coagulation, complement activation, and cellular matrix loss.

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