The role of selectins in glomerular leukocyte recruitment in rat anti-glomerular basement membrane glomerulonephritis

Leukocytes play a central role in the pathogenesis of anti-glomerular basem ent membrane glomerulonephritis (anti-GBM GN). Understanding the mechanisms underlying their recruitment in the glomerulus is of critical importance, because this may lead to more specific anti-inflammatory drug design. The r equirement for integrins, especially from the beta(2) group, and their Ig s uperfamily counter-receptors has been established, however, the role of sel ectins remains controversial. An intravital microscopy technique was develo ped to study concomitantly the glomerular and venular leukocyte kinetics an d the hemodynamic alterations in a rat model of anti-GBM GN, induced by inj ection of 10 mg of nephrotoxic serum (NTS). Histologic studies of the kidne y were performed in parallel and urinary protein excretion was measured. Th e animals received NTS alone or were pretreated with either a monoclonal an tibody against the beta(2) integrin CD11b (OX42, 4 mg/kg) or fucoidan F7 (F F7, 8 mg/kg), an oligosaccharide that blocks both L- and P-selectin functio n. Administration of NTS resulted in a time-dependent increase in the numbe r of adherent leukocytes in the glomeruli and a parallel decrease of the pe rfused glomerular capillary area. Substantial proteinuria was observed. Pre treatment with OX42 significantly attenuated these changes. FF7 almost abol ished the rolling of the leukocytes in the venules, thus demonstrating effi cient anti-selectin activity. Nevertheless, FF7 had no influence on the glo merular events or on the development of proteinuria. These results confirm that glomerular leukocyte adhesion in anti-GEM GN is CD11b-dependent. Howev er, selectin-mediated interaction between the leukocytes and the glomerular capillary endothelium does not appear to be a prerequisite for leukocyte a dhesion in the glomerulus. These results therefore question the potential u tility of anti-selectin therapy in the treatment of anti-GEM GN.