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Passive Heymann nephritis (PHN) is a complementdependent model of immune complex glomerulonephritis. This study investigated the contribution of local complement synthesis by studying gene expression of the classical pathway component C4 in relation to the site of the tissue injury and the development of proteinuria induced by the pathogenic antibody (sheep anti-GP330). This study, using in situ hybridization, found that C4 mRNA expression was increased in the glomerular epithelium and the proximal renal tubular epithelium in a distribution similar to that of the targeted GP330 antigen. The total cortical C4 mRNA expression assessed by semiquantitative polymerase chain reaction (PCR) increased in a timedependent manner (P < 0.05), coincident with the onset and progression of proteinuria, and peaking 1 1 to 14 days after the induction of the disease. These data suggest a link, in place and time, between local complement gene expression and glomerular barrier dysfunction induced by anti-GP330. It is postulated that increased epithelial synthesis of C4 stimulated by the engagement of GP330 enhances the formation of the membrane attack complex of complement through its classical pathway, and, hence, the formation of complement-mediated injury. (J Am Soc Nephrol 8: 214-222, 1997) Numerous studies have shown that complement plays a role in the pathogenesis of passive Heymann nephritis (1). In this model, membranous glomerulonephritis is induced by antiGP330 antibody binding to the glomerular epithelium. Inhibition or depletion of the early components of complement activation prevents the development of proteinuria without interfering with immune-complex formation (2). Assembly of the terminal attack complex of complement, C5b-9, is thought to be an important effector mechanism in experimental membranous nephropathy (3,4), whereas the fourth component of complement, C4, is an essential component of the classical (antibody-mediated) pathway of complement activation, leading to the formation of the membrane attack complex. The split product C4b is an important site for amplification and control of the complement cascade, and C4a has mild anaphylotoxic properties. Most plasma C4 is synthesized in the liver, but smaller amounts are produced in other tissues [reviewed in (5)], including glomerular epithelial cells (GEC), mesangial cells, and proximal tubule epithelial cells (PTEC) (6-8). Synthesis and secretion of C4 by cultured glomerular cells occurs spontaneously or upon stimulation with proinflammatory cytokines. The question remains as to the functional relevance of local Received April 29, 1996. Accepted October 23, 1996. Correspondence to Dr. S.H. Sacks, Renal Unit, Guy’s Hospital, London SE1 9RT, U.K. 1046-6673/0802-02 l4$03.00/0 Journal of the American Society of Nephrology Copyright (
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