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 opportuni ties. 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 neph rotoxic nephritis, glomerular expression of VCAM-1, studied by immunohistoc hemistry, was up-regulated by day 6 of nephritis, To quantify kidney endoth elial 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 elevate d until at least day 28, An in vivo study was then performed, using blockin g mAbs to either VCAM-1 or VLA-4, starting mAb treatment on the day prior t o disease induction, and continuing until animals were sacrificed at day 7, mAbs to VLA-4 significantly attenuated renal injury (albuminuria, glomerul ar fibrinoid necrosis, and crescent formation), but mAbs to VCAM-1 had no s ignificant effect. Surprisingly, the number of leukocytes within glomeruli was unaffected by anti-VLA-4 mAb therapy, despite the reduction in renal in jury. Paradoxically, classical markers of macrophage activation were increa sed in the anti-VLA-4- and anti-VCAM-1-treated animals. This study demonstr ates that kidney endothelial VCAM-1, in contrast to ICAM-1, is not up-regul ated by day 2 of nephrotoxic nephritis, and plays little part in early leuk ocyte influx into glomeruli, However, VLA-4 is an important mediator of glo merular injury, operating after transendothelial leukocyte migration, and p resumably binding to alternate ligands within the kidney.