Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium.
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.
Asgeirsdóttir
Sigridur A
SA
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
Kamps
Jan A A M
JA
Bakker
Hester I
HI
Zwiers
Peter J
PJ
Heeringa
Peter
P
van der Weide
Karen
K
van Goor
Harry
H
Petersen
Arjen H
AH
Morselt
Henriëtte
H
Moorlag
Henk E
HE
Steenbergen
E
E
Kallenberg
Cees G
CG
Molema
Grietje
G
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
D019040:E-Selectin; D007074:Immunoglobulin G; D008081:Liposomes; D019010:Vascular Cell Adhesion Molecule-1; D003907:Dexamethasone