The objective of the research proposed in this application is to understand the role of the complement system in immune-mediated glomerulonephritis (GN). The two rat models of GN that will be studied are Heymann nephritis (HN), a model of membranous nephropathy, and immune complex (IC) GN which models lupus, post-infectious and membranoproliferative GN. Considerable evidence exists that complement is important in the pathogenesis of these diseases in experimental animals and in humans. All glomerular cells have intrinsic complement regulatory proteins. Antibodies to these proteins can block their function, thereby enhancing complement activation. Evidence exists that such antibodies occur in HN, which represents a unique pathogenic mechanism. The first specific aim will examine whether the injected antibodies (in passive HN) and autoantibodies (produced in active HN) to these complement regulators are essential to the pathogenesis of these diseases. ICGN is characterized by inflammatory cell infiltration into glomeruli and intrinsic glomerular cell injury. In this model, systemic and glomerular complement activation occurs. The second specific aim will examine the role complement activation has in the pathogenesis of ICGN. To do this, complement will be completely inhibited with recombinant rat Crry (complement receptor related [protein] y) over the disease course. The effect of such complement inhibition to reduce disease outcomes, such as the elevated serum creatinine and substantial proteinuria will be determined. The interaction of the complement system with other inflammatory mediators will also be evaluated, which will identify whether complement is a proximate mediator, as suggested by short-term GN models, or acts in parallel with other effector systems. Complement receptor 1 (CR1) in humans appears to be responsible for processing immune complexes. The functional analogues in rodents are proteins known as C3bR-200 and C3bR-165. The goal of the third specific aim is to further characterize these proteins. The amino acid compositions of these proteins will be directly determined. The cDNA for these proteins will be cloned using available antibody and nucleotide probes. The role for these proteins to process immune complexes in vitro will be evaluated using the ICGN model. Because of the similarities between these chronic disease models and the analogous human conditions, completion of the research proposed in this application will provide information on the pathogenesis of GN in humans. Given the availability of complement inhibitors as therapeutics, it is possible that these could be useful for GN, which will be directly evaluated.
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