FIBRINOGEN MEDIATES PLATELET-POLYMORPHONUCLEAR LEUKOCYTE COOPERATION DURING IMMUNE-COMPLEX GLOMERULONEPHRITIS IN RATS

The metabolic and functional alterations which occur during the acute phase of nephrotoxic nephritis (NTN) in rats, a model of immune-mediat ed glomerulonephritis, result from a cooperative interaction between P MNs and platelets (PLTs). In consequence, we hypothesized that fibrino gen (Fg) might play a critical role in this process and, accordingly, we found that defibrination of animals decreased both the acute phase proteinuria in NTN (similar to 70%) as well as the influx of PLTs and PMNs into the glomerulus (similar to 40-50%). In contrast, blockade of the PLT Fg receptor, alpha(IIb) beta(3), with the RGD peptidomimetic SC-49992 decreased proteinuria (similar to 90%) without substantially altering the influx of PMNs or PLTs. Immunocytochemistry showed a mark ed increase in beta(3) integrin expression in inflamed glomeruli which was prevented either by PMN or PLT depletion before disease induction . FACS(R) and immunocytochemical analysis of glomerular cell dissociat es demonstrated that beta(3) integrin expression was predominantly on intraglomerular PLTs. In vitro, activated PLTs stimulated the PMN resp iratory burst, an interaction which could be inhibited by Fg receptor blockade. In sum, acute NTN is accompanied by a marked increase in glo merular beta(3) integrin expression predominantly due to the influx of PLTs which localize to the glomerulus in a PMN-dependent fashion. Fg appears to serve a major role as a coactivating stimulus for PLT-PMNs in situ via alpha(IIb)beta(3), potentially mediating the PMN respirato ry burst which contributes to proteinuria. Fg may also play a subsidia ry role in PMN/PLT comigration.