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First published on April 23, 2007; DOI: 10.1124/mol.107.034140

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Received for publication January 16, 2007.
Revised April 22, 2007.
Accepted for publication April 23, 2007.

Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium

Sigridur A. Asgeirsdottir 1*, Jan A. A. M. Kamps 1, Hester I. Bakker 1, Peter J. Zwiers 1, Peter Heeringa 1, Karen van der Weide 1, Harry van Goor 1, Arjen Petersen 1, Henriette Morselt 2, Hendrik E. Moorlag 1, Eric Steenbergen 3, Cees G. M. Kallenberg 1, Grietje Molema 1

1 University Medical Center, Groningen, University of Groningen, The Netherlands 2 University Medical Center, Groningen, University of Groningen,The Netherlands 3 Radboud University Nijmegen Medical Centre, The Netherlands

* Address correspondence to: E-mail: s.a.asgeirsdottir{at}med.umcg.nl

Abstract

Glomerulonephritis represents a group of renal diseases with glomerular inflammation as a common pathologic finding. Due to the underlying immunologic character of these disorders, they are frequently treated with glucocorticoids and cytotoxic immunosuppressive agents. Although effective, use of these compounds has limitations due to toxicity and systemic side effects. In the current study we tested the hypothesis that targeted delivery of dexamethasone (dexa) by immunoliposomes to activated glomerular endothelium decreases renal injury while preventing its systemic side effects. E-selectin was chosen as a target molecule based on its disease specific expression on activated glomerular endothelium in a mouse anti-glomerular basement membrane glomerulonephritis. Site selective delivery of AbEsel-liposomes encapsulated dexamethasone strongly reduced glomerular proinflammatory gene expression without affecting blood glucose levels, a severe side effect of administration of free dexamethasone. Dexa-AbEsel-liposomes reduced renal injury as shown by a reduction of blood ureum nitrogen levels, decreased glomerular crescent formation and downregulation of disease associated genes. Immunoliposomal drug delivery to glomerular endothelium presents a powerful new strategy for treatment of glomerulonephritis to sustain efficacy and prevent side effects of potent anti-inflammatory drugs.


Key words: Glucorticoids/Mineralocorticoids, Regulation of gene expression, Liposome, Antibody, Receptor-mediated


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 Am. J. Physiol. Renal Physiol.Home page
S. A. Asgeirsdottir, P. J. Zwiers, H. W. Morselt, H. E. Moorlag, H. I. Bakker, P. Heeringa, J. W. Kok, C. G. M. Kallenberg, G. Molema, and J. A. A. M. Kamps
Inhibition of proinflammatory genes in anti-GBM glomerulonephritis by targeted dexamethasone-loaded AbEsel liposomes
Am J Physiol Renal Physiol, March 1, 2008; 294(3): F554 - F561.
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