C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis

We studied the role of the C5b-9 membrane attack complex in two models of i nflammatory glomerulonephritis (GN) initiated by acute glomerular endotheli al injury in Piebold-viral-Glaxo (PVG) complement-sufficient rats (C+), CG- deficient rats (C6-), and rats systematically depleted of complement with c obra venom factor (CVF). GN was induced by performing a left nephrectomy an d selectively perfusing the right kidney with either 1) the lectin concanav alin A (Con A) followed by complement-fixing anti-Con A (Con A GN) or 2) pu rified complement-fixing goat anti-rat glomerular endothelial cell (GEN) an tibody [immune-mediated thrombotic microangiopathy (ITM)]. Comparable level s of GEN apoptosis were detected in C+ animals in both models. CVF administ ration reduced GEN apoptosis by 10- to 12-fold. GEN apoptosis was C5b-9 dep endent because PVG C6- rats were protected from GEN loss. Furthermore, func tional inhibition of the cell surface complement regulatory protein CD59 by renal perfusion with anti-CD59 antibody in ITM resulted in a 3.5-fold incr ease in GEN apoptosis. Last, in Con A GN, abrogation of GEN apoptosis prese rved endothelial integrity and renal function. This study demonstrates the specific role of C5b-9 in the induction of GEN apoptosis in experimental in flammatory GN, a finding with implications for diseases associated with the presence of antiendothelial cell antibodies.