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. 1983 Dec;72(6):1948–1957. doi: 10.1172/JCI111159

Role of the terminal complement pathway in experimental membranous nephropathy in the rabbit.

G C Groggel, S Adler, H G Rennke, W G Couser, D J Salant
PMCID: PMC437035  PMID: 6227634

Abstract

Our recent observations of a complement-mediated, cell-independent mechanism of altered glomerular permeability in rat membranous nephropathy suggested a possible role for the terminal complement pathway in the mediation of proteinuria in certain forms of glomerular disease. To directly determine whether the membranolytic terminal complement components (C5b-C9) are involved in glomerular injury, we studied the development of proteinuria in normal and C6-deficient (C6D) rabbits, in both of which a membranous nephropathy-like lesion develops early in the course of immunization with cationized bovine serum albumin (cBSA) (pI 8.9-9.2). C6 hemolytic activity of C6D was 0.01% that of control rabbits. After 1 wk of daily intravenous injections of cBSA, proteinuria developed in 71% of controls (median 154, range 1-3,010 mg/24 h, n = 24), whereas none of C6D were proteinuric (median 6, range 2-12 mg/24 h, n = 12, P less than 0.01). After 1 wk of cBSA, both groups had qualitatively identical glomerular deposits of BSA, rabbit IgG, and C3 on immunofluorescence microscopy, predominantly subepithelial electron-dense deposits on electron microscopy, and minimal glomerular inflammatory cell infiltration of glomeruli. Glomeruli were isolated from individual animals after 1 wk of cBSA and deposits of rabbit IgG antibody were quantitated by a standardized in vitro assay using anti-rabbit IgG-125I. Rabbit IgG deposits were found to be similar in control (29.8 +/- 13.2, range 12.7-48.6 micrograms anti-IgG/2,000 glomeruli, n = 6) and C6D rabbits (32.6 +/- 13.8, range 16.8-48.8 micrograms anti-IgG/2,000 glomeruli, n = 5, P greater than 0.05). After 2 wk, coincident with a prominent influx of mononuclear cells and neutrophils, proteinuria developed in C6D rabbits. These results document, for the first time, a requirement for a terminal complement component in the development of immunologic glomerular injury. Since the only known action of C6 is in the assembly of the membrane attack complex, these observations suggest that the membranolytic properties of complement may contribute to glomerular damage.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adler S. G., Wang H., Ward H. J., Cohen A. H., Border W. A. Electrical charge. Its role in the pathogenesis and prevention of experimental membranous nephropathy in the rabbit. J Clin Invest. 1983 Mar;71(3):487–499. doi: 10.1172/JCI110793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Biesecker G., Katz S., Koffler D. Renal localization of the membrane attack complex in systemic lupus erythematosus nephritis. J Exp Med. 1981 Dec 1;154(6):1779–1794. doi: 10.1084/jem.154.6.1779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Biesecker G., Lavin L., Ziskind M., Koffler D. Cutaneous localization of the membrane attack complex in discoid and systemic lupus erythematosus. N Engl J Med. 1982 Feb 4;306(5):264–270. doi: 10.1056/NEJM198202043060503. [DOI] [PubMed] [Google Scholar]
  4. Border W. A., Ward H. J., Kamil E. S., Cohen A. H. Induction of membranous nephropathy in rabbits by administration of an exogenous cationic antigen. J Clin Invest. 1982 Feb;69(2):451–461. doi: 10.1172/JCI110469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Couser W. G., Steinmuller D. R., Stilmant M. M., Salant D. J., Lowenstein L. M. Experimental glomerulonephritis in the isolated perfused rat kidney. J Clin Invest. 1978 Dec;62(6):1275–1287. doi: 10.1172/JCI109248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Edgington T. S., Glassock R. J., Dixon F. J. Autologous immune complex nephritis induced with renal tubular antigen. I. Identification and isolation of the pathogenetic antigen. J Exp Med. 1968 Mar 1;127(3):555–572. doi: 10.1084/jem.127.3.555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Forbes R. D., Guttmann R. D. Evidence for complement-induced endothelial injury in vivo: a comparative ultrastructural tracer study in a controlled model of hyperacute rat cardiac allograft rejection. Am J Pathol. 1982 Mar;106(3):378–387. [PMC free article] [PubMed] [Google Scholar]
  8. Forbes R. D., Guttmann R. D., Kuramochi T., Klassen J., Knaack J. Nonessential role of neutrophils as mediators of hyperacute cardiac allograft rejection in the rat. Lab Invest. 1976 Mar;34(3):229–234. [PubMed] [Google Scholar]
  9. Forbes R. D., Pinto-Blonde M., Guttmann R. D. The effect of anticomplementary cobra venom factor on hyperacute rat cardiac allograft rejection. Lab Invest. 1978 Nov;39(5):463–470. [PubMed] [Google Scholar]
  10. Hoare D. G., Koshland D. E., Jr A method for the quantitative modification and estimation of carboxylic acid groups in proteins. J Biol Chem. 1967 May 25;242(10):2447–2453. [PubMed] [Google Scholar]
  11. Inoue K., Kinoshita T., Okada M., Akiyama Y. Release of phospholipids from complement-mediated lesions on the surface structure of Escherichia coli. J Immunol. 1977 Jul;119(1):65–72. [PubMed] [Google Scholar]
  12. Kerjaschki D., Farquhar M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med. 1983 Feb 1;157(2):667–686. doi: 10.1084/jem.157.2.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kerjaschki D., Farquhar M. G. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5557–5561. doi: 10.1073/pnas.79.18.5557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kolb W. P., Muller-Eberhard H. J. The membrane attack mechanism of complement. Isolation and subunit composition of the C5b-9 complex. J Exp Med. 1975 Apr 1;141(4):724–735. [PMC free article] [PubMed] [Google Scholar]
  15. Mancini G., Carbonara A. O., Heremans J. F. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry. 1965 Sep;2(3):235–254. doi: 10.1016/0019-2791(65)90004-2. [DOI] [PubMed] [Google Scholar]
  16. McConahey P. J., Dixon F. J. A method of trace iodination of proteins for immunologic studies. Int Arch Allergy Appl Immunol. 1966;29(2):185–189. doi: 10.1159/000229699. [DOI] [PubMed] [Google Scholar]
  17. O'Regan C. C., Robitaille P., Pinto-Blonde M., Chartrand C. Delayed rejection of cardiac xenografts in C6-deficient rabbits. Immunology. 1979 Oct;38(2):245–248. [PMC free article] [PubMed] [Google Scholar]
  18. Podack E. R., Tschoop J., Müller-Eberhard H. J. Molecular organization of C9 within the membrane attack complex of complement. Induction of circular C9 polymerization by the C5b-8 assembly. J Exp Med. 1982 Jul 1;156(1):268–282. doi: 10.1084/jem.156.1.268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rennke H. G., Olson J. L., Venkatachalam M. A. Glomerular filtration of macromolecules: normal mechanisms and the pathogenesis of proteinuria. Contrib Nephrol. 1981;24:30–41. doi: 10.1159/000395227. [DOI] [PubMed] [Google Scholar]
  20. Salant D. J., Belok S., Madaio M. P., Couser W. G. A new role for complement in experimental membranous nephropathy in rats. J Clin Invest. 1980 Dec;66(6):1339–1350. doi: 10.1172/JCI109987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Salant D. J., Darby C., Couser W. G. Experimental membranous glomerulonephritis in rats. Quantitative studies of glomerular immune deposit formation in isolated glomeruli and whole animals. J Clin Invest. 1980 Jul;66(1):71–81. doi: 10.1172/JCI109837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Snyderman R., Phillips J., Mergenhagen S. E. Polymorphonuclear leukocyte chemotactic activity in rabbit serum and Guinea pig serum treated with immune complexes: evidence for c5a as the major chemotactic factor. Infect Immun. 1970 Jun;1(6):521–525. doi: 10.1128/iai.1.6.521-525.1970. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Van Damme B. J., Fleuren G. J., Bakker W. W., Vernier R. L., Hoedemaeker P. J. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis. Lab Invest. 1978 Apr;38(4):502–510. [PubMed] [Google Scholar]
  24. Zimmerman T. S., Arroyove C. M., Müller-Eberhard H. J. A blood coagulation abnormality in rabbits deficient in the sixth component of complement (C6) and its correction by purified C6. J Exp Med. 1971 Dec 1;134(6):1591–1600. doi: 10.1084/jem.134.6.1591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Zimmerman T. S., Müller-Eberhard H. J. Blood coagulation initiation by a complement-mediated pathway. J Exp Med. 1971 Dec 1;134(6):1601–1607. doi: 10.1084/jem.134.6.1601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. van Es L. A., Blok A. P., Schoenfield L., Glassock R. J. Chronic nephritis induced by antibodies reacting with glomerular-bound immune complexes. Kidney Int. 1977 Feb;11(2):106–115. doi: 10.1038/ki.1977.15. [DOI] [PubMed] [Google Scholar]

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