Endothelial expression of VCAM-1 in experimental crescentic nephritis and effect of antibodies to very late antigen-4 or VCAM-1 on glomerular injury.
The migration of leukocytes into glomeruli in crescentic glomerulonephritis is fundamental to pathogenesis, and offers important therapeutic opportunities. We addressed the importance of VCAM-1, and its leukocyte ligand very late antigen-4 (VLA-4), in such leukocyte migration. In a rat model of nephrotoxic nephritis, glomerular expression of VCAM-1, studied by immunohistochemistry, was up-regulated by day 6 of nephritis. To quantify kidney endothelial VCAM-1 expression, a differential radiolabeled mAb technique was used, which demonstrated that protein expression was not up-regulated by day 2 of nephritis, but rose threefold between days 2 and 5, and remained elevated until at least day 28. An in vivo study was then performed, using blocking mAbs to either VCAM-1 or VLA-4, starting mAb treatment on the day prior to disease induction, and continuing until animals were sacrificed at day 7. mAbs to VLA-4 significantly attenuated renal injury (albuminuria, glomerular fibrinoid necrosis, and crescent formation), but mAbs to VCAM-1 had no significant effect. Surprisingly, the number of leukocytes within glomeruli was unaffected by anti-VLA-4 mAb therapy, despite the reduction in renal injury. Paradoxically, classical markers of macrophage activation were increased in the anti-VLA-4- and anti-VCAM-1-treated animals. This study demonstrates that kidney endothelial VCAM-1, in contrast to ICAM-1, is not up-regulated by day 2 of nephrotoxic nephritis, and plays little part in early leukocyte influx into glomeruli. However, VLA-4 is an important mediator of glomerular injury, operating after transendothelial leukocyte migration, and presumably binding to alternate ligands within the kidney.
Allen
A R
AR
Renal Section, Division of Medicine, British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Medicine, London, United Kingdom. a.allen@rpms.ac.uk
McHale
J
J
Smith
J
J
Cook
H T
HT
Karkar
A
A
Haskard
D O
DO
Lobb
R R
RR
Pusey
C D
CD
D000419:Albuminuria / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D007150:Immunohistochemistry; D039041:Integrin alpha4beta1; D016023:Integrins / Q000276:immunology* / Q000502:physiology; D007457:Iodine Radioisotopes / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D016201:Receptors, Lymphocyte Homing / Q000276:immunology* / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D039041:Integrin alpha4beta1; D016023:Integrins; D007457:Iodine Radioisotopes; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1