A new role for complement in experimental membranous nephropathy in rats

The only established role for complement in mediating immunologic renal disease involves elaboration of leukochemotactic factors and neutrophil-dependent glomerular injury. In the passive Heymann nephritis (PHN) model of experimental membranous nephropathy, rats injected with sheep antibody to rat proximal tubular brush border antigen (Fx1A) form subepithelial deposits of sheep IgG and rat complement (C3), and develop heavy proteinuria after 5 d without glomerular inflammatory changes. To study the role of complement in mediating proteinuria in PHN, 16 rats were treated daily with cobra venom factor from before antibody injection to maintain C3 levels at < 10% of pretreatment values and compared to 16 untreated controls. Proteinuria at 5 d was abolished in C3-depleted rats (4 +/- 1, controls 70 +/- 15 mg/d, P < 0.001), although renal deposition of 125I-labeled antibody ws the same in both groups (188 +/- 35 vs. 191 +/- 22 microgram IgG/2 kidneys, P > 0.5). Nephritogenic doses of both the noncomplement-fixing F(ab')2 portion and the gamma 2 subclass of anti-Fx1A IgG produced subepithelial deposits of immunoglobulin without C3, but proteinuria did not occur despite glomerular deposition of up to 70 microgram/2 kidneys of gamma 2. However, glomerular deposition of as little as 60 microgram of gamma 1 produced C3 fixation in vivo and heavy proteinuria. No neutrophil exudate could be detected histologically in PHN from the time of antibody injection through development of proteinuria. Proteinuria in five PHN rats depleted of neutrophils to < 200/mm3 with antineutrophil serum was not reduced compared to six controls with normal neutrophil counts (34 +/- 9.6 vs. 25 +/- 10.4 mg/d, P > 0.5). These results demonstrate that proteinuria in the PHN model of membranous nephropathy is complement-dependent and strongly suggest a neutrophil-independent mechanism. Thus a new role for the complement system in mediating immunologic glomerular injury is identified.