Heymann nephritis is a rat model of membranous nephropathy induced by a single immunization with a crude preparation of renal tubular epithelial antigens. Studies of the immunopathogenesis of this model have shown that several antigen-antibody systems contribute to the formation of subepithelial immune deposits. Two of these antigen-antibody systems have a special inter-relationship, as the antigens and their respective antibodies and anti-idiotypic antibodies bind to each other through reciprocating internal images. The development of anti-idiotypic antibodies (Ab2) which mimic antigen (Ag1) augment continued synthesis of Ab1. Ag1 is a tubular antigen that binds to a glomerular antigen (Ag2). Ag2 (gec-gp140) is a basic (pI 9.2) membrane protein unique to the glomerular epithelial cell, is shed into Bowmans space and can be detected in urine. When perfused into isolated proximal renal tubules, preliminary data show that gec-gp140 inhibits proximal reabsorption of sodium by 20-40%. These observations suggest the following hypothesis: Hypothesis: 1) The unique features of these antigen-antibody systems contribute to the immunopathogenesis of Heymann nephritis. 2) gec-gp140 is synthesized and secreted by the glomerular epithelial cell into Bowmans space, whereby it enters the tubular lumen, binds to the proximal tubular membrane and alters tubular reabsorption of sodium. Objective 1: Biochemical characterization of gec-gp140, including amino acids sequence determination and analysis of post-translational modifications using biosynthetic labelling techniques. Objective 2: Determination of regulation of synthesis of gec-gp140; in vivo, using animal models of glomerular injury, and in vitro, using glomerular epithelial cells in culture. Objective 3: Confirmation of the influence of gec-gp140 on tubular function, by repetition of tubule perfusion studies. Data obtained from these studies will provide knowledge of the normal physiologic function of these proteins which participate as antigens in the immunopathogenesis of Heymann nephritis.
