ROLE OF THE COMPLEMENT MEMBRANE ATTACK COMPLEX (C5B-9) IN MEDIATING EXPERIMENTAL MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS

Previous studies have demonstrated that most pathologic changes in the antithymocyte serum (ATS) model of mesangioproliferative glomerulonep hritis are complement-dependent. These include mesangiolysis, glomerul ar platelet infiltration, mesangial cell proliferation, mesangial cell production of growth factors and phenotypic change to express alpha-a ctin, glomerular macrophage infiltrate, mesangial matrix expansion, an d proteinuria. The mechanism by which complement mediates these effect s has not been defined. Because neutrophils do not participate in the ATS model, we hypothesized that the complement effects observed are co nsequent to glomerular cell insertion of the C5b-9 membrane attack com plex of complement. This hypothesis was tested utilizing PVG rats whic h exhibit an absence of C6 inherited in an autosomal recessive pattern . C6 deficient (C-) PVG rat serum activated by zymosan produced normal amounts of C5a compared to normocomplementemic (C+) PVG rat controls but no C5b-9. When ATS was induced, C- PVG rats had a significant and marked reduction in mesangiolysis, platelet infiltration, mesangial ce ll proliferation, alpha-actin expression, macrophage infiltration, col lagen IV deposition, and proteinuria compared to C+ controls. The redu ction in each of these parameters was comparable to that achieved by s ystemic complement depletion of C+ PVG rats with cobra venom factor. T hese findings establish the role of C5b-9 in mediating each of the com plement-dependent features of the ATS model and indicate that C5b-9 ac counts for all of the complement-mediated effects observed. This study provides the first documentation of a functional role for C5b-9 in me diating a non-membranous inflammatory type of glomerular injury in viv o.