title: Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium.
abstract: Glomerulonephritis represents a group of renal diseases with glomerular inflammation as a common pathologic finding. Because of 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 as a result of 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 but prevents 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 Ab(Esel) liposome-encapsulated dexamethasone strongly reduced glomerular proinflammatory gene expression without affecting blood glucose levels, a severe side effect of administration of free dexamethasone. Dexa-Ab(Esel) liposomes reduced renal injury as shown by a reduction of blood urea nitrogen levels, decreased glomerular crescent formation, and down-regulation 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.
authors: Medical Biology Section, Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. s.a.asgeirsdottir@med.umcg.nl
authors: Sigridur A
authors: SA
authors: Asgeirsdóttir
authors: Jan A A M
authors: JA
authors: Kamps
authors: Hester I
authors: HI
authors: Bakker
authors: Peter J
authors: PJ
authors: Zwiers
authors: Peter
authors: P
authors: Heeringa
authors: Karen
authors: K
authors: van der Weide
authors: Harry
authors: H
authors: van Goor
authors: Arjen H
authors: AH
authors: Petersen
authors: Henriëtte
authors: H
authors: Morselt
authors: Henk E
authors: HE
authors: Moorlag
authors: E
authors: E
authors: Steenbergen
authors: Cees G
authors: CG
authors: Kallenberg
authors: Grietje
authors: G
authors: Molema
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage*; D018450:Disease Progression; D019040:E-Selectin / Q000276:immunology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D050533:Glomerular Basement Membrane / Q000276:immunology; D005921:Glomerulonephritis / Q000188:drug therapy*; D007074:Immunoglobulin G / Q000008:administration & dosage*; D007678:Kidney Glomerulus / Q000187:drug effects*; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D019040:E-Selectin; D007074:Immunoglobulin G; D008081:Liposomes; D019010:Vascular Cell Adhesion Molecule-1; D003907:Dexamethasone