Mediation of proteinuria in membranous nephropathy due to a planted glomerular antigen

In experimental membranous nephropathy in rats (passive Heymann nephritis) subepithelial immune deposits result from in situ reaction of heterologous (sheep) antibody against rat proximal tubular brushborder antigen (Fx1A) with an endogenous glomerular antigen. We have previously shown that the proteinuria which results is complement-dependent but neutrophil-independent. To investigate the mediation of glomerular injury induced when subepithelial deposits result from antibody binding to an exogenous antigen planted in the glomerulus, rats were injected with subnephritogenic doses of noncomplement fixing sheep γ2 anti-rat Fx1A IgG which produced subepithelial deposits of sheep IgG without morphologic or functional evidence of glomerular injury. When kidneys from these donor rats were transplanted into bilaterally nephrectomized recipients preimmunized with sheep IgG, the deposits of sheep IgG served as a planted antigen to initiate subepithelial immune complex formation and proteinuria. Five days after transplantation, recipients of antigen-containing kidneys had subepithelial deposits of sheep IgG, rat IgG, rat C3, and proteinuria. Proteinura did not occur at 5 days in recipients of antigen-containing kidneys that were immunosuppressed by sublethal irradiation or complement-depleted with cobra venom factor (CVF); recipients of normal rat kidneys were not proteinuric. When recipients of antigen-containing kidneys were passively immunized with rat anti-sheep IgG, proteinuria at 2 days was not affected by either selective neutrophil depletion or pancytopenia induced by lethal irradiation. Proteinuria was also complement-dependent in intact rats in which in situ subepithelial immune complex formation was induced in 7 to 8 days by preimmunization with sheep IgG followed by injection of γ2 sheep anti-rat Fx1A. These results demonstrate that glomerular injury in experimental membranous nephropathy in rats is complement-dependent but cell-independent when deposit formation is initiated by antibody reacting with an exogenous sheep IgG antigen planted in the glomerulus as well as with an endogenous glomerular antigen. They suggest that this new mechanism of glomerular injury may be relevant to all forms of membranous nephropathy.