Fibrinogen mediates platelet-polymorphonuclear leukocyte cooperation during immune-complex glomerulonephritis in rats

Abstract

The metabolic and functional alterations which occur during the acute phase of nephrotoxic nephritis (NTN) in rats, a model of immune-mediated glomerulonephritis, result from a cooperative interaction between PMNs and platelets (PLTs). In consequence, we hypothesized that fibrinogen (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 (~ 70%) as well as the influx of PLTs and PMNs into the glomerulus (~ 40- 50%). In contrast, blockade of the PLT Fg receptor, α(IIb) β3, with the RGD peptidomimetic SC-49992 decreased proteinuria (~ 90%) without substantially altering the influx of PMNs or PLTs. Immunocytochemistry showed a marked increase in β3 integrin expression in inflamed glomeruli which was prevented either by PMN or PLT depletion before disease induction. FACS® and immunocytochemical analysis of glomerular cell dissociates demonstrated that β3 integrin expression was predominantly on intraglomerular PLTs. In vitro, activated PLTs stimulated the PMN respiratory burst, an interaction which could be inhibited by Fg receptor blockade. In sum, acute NTN is accompanied by a marked increase in glomerular β3 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 α(IIb)β3, potentially mediating the PMN respiratory burst which contributes to proteinuria. Fg may also play a subsidiary role in PMN/PLT comigration.