In passive Heymann nephritis, a rat model of human membranous nephropathy, antibody (anti-Fx1A) activates complement on the surface of the glomerular visceral epithelial cell (GEC), with resultant cell injury and, consequently, the development of proteinuria. GEC in culture contain membrane proteins that limit complement activation. It is likely that these proteins are also present in vivo and serve to protect the GEC from both spontaneous and antibody-directed complement activation. Evidence exists that anti-Fx1A is particularly effective in activating complement on GEC by virtue of its binding to, and inhibiting, a complement regulatory protein of the GEC. In order to isolate these proteins with complement inhibitory activity, membrane proteins from cultured rat GEC will be subjected to various chromatographic steps. The ability to inhibit complement in a hemolytic assay will guide isolation of these proteins. Antibodies to purified proteins will then be raised and tested for their ability to inhibit the regulation of complement, thereby enhancing complement activation, in vitro. Studies will also be performed in vivo with these antibodies to explore the role complement regulation has in protecting GEC under normal circumstances and in a disease dependent upon complement activation, passive Heymann nephritis. The particular complement regulatory protein identified by anti-Fx1A will also be isolated. The role that inhibition of its normal function plays in passive Heymann nephritis will be established. The ability of the GEC to respond to complement activation by increasing membrane expression of these regulatory proteins will be determined in vitro,. Lastly, the capability of the GEC to eliminate antibody that has bound to, and inhibited, a complement regulatory protein of the surface of the cell, will be evaluated.
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