Logo of jexpmedHomeThe Rockefeller University PressEditorsContactInstructions for AuthorsThis issue
J Exp Med. Apr 1, 1993; 177(4): 905–914.
PMCID: PMC2190976

Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model

Abstract

To develop an animal model for antimyeloperoxidase (MPO)-associated necrotizing crescentic glomerulonephritis (NCGN), we immunized Brown Norway rats with MPO and localized a neutrophil lysosomal enzyme extract, primarily consisting of MPO and elastinolytic enzymes, plus H2O2, the substrate of MPO, to the glomerular basement membrane (GBM). Upon immunization rats developed antibodies and positive skin tests to MPO. After unilateral perfusion of the left kidney with the lysosomal enzyme extract and H2O2, MPO and immunoglobulin (Ig)G localized transiently along the GMB. At the time of maximal inflammation, at 4 and 10 d after perfusion, MPO, IgG, and C3 could not be detected anymore. MPO-immunized rats perfused with the lysosomal enzyme extract and H2O2, in contrast to control-immunized and/or control-perfused rats, developed a proliferative GN characterized by intra- and extracapillary cell proliferation, ruptured Bowman's capsule, periglomerular granulomatous inflammation, and formation of giant cells. Monocytes, polymorphonuclear leukocytes (PMN), and to a far lesser extent T cells were found in the glomeruli. Interstitial infiltrates consisted of monocytes, PMN, and T cells. Granulomatous vasculitis of small vessels was found at 10 d after perfusion. The proliferative NCGN in this rat model closely resembles human anti-MPO- associated pauci-immune NCGN, and enables the study of the pathophysiology of anti-MPO-associated NCGN.

Full Text

The Full Text of this article is available as a PDF (2.4M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Couser WG. Idiopathic rapidly progressive glomerulonephritis. Am J Nephrol. 1982;2(2):57–69. [PubMed]
  • Falk RJ. ANCA-associated renal disease. Kidney Int. 1990 Nov;38(5):998–1010. [PubMed]
  • Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, Hack CE, van den Ende ME, Kallenberg CG, von dem Borne AE. Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest. 1989 Nov;84(5):1577–1587. [PMC free article] [PubMed]
  • Niles JL, McCluskey RT, Ahmad MF, Arnaout MA. Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood. 1989 Nov 1;74(6):1888–1893. [PubMed]
  • Lüdemann J, Utecht B, Gross WL. Anti-neutrophil cytoplasm antibodies in Wegener's granulomatosis recognize an elastinolytic enzyme. J Exp Med. 1990 Jan 1;171(1):357–362. [PMC free article] [PubMed]
  • Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med. 1988 Jun 23;318(25):1651–1657. [PubMed]
  • Tervaert JW, Goldschmeding R, Elema JD, van der Giessen M, Huitema MG, van der Hem GK, The TH, von dem Borne AE, Kallenberg CG. Autoantibodies against myeloid lysosomal enzymes in crescentic glomerulonephritis. Kidney Int. 1990 Feb;37(2):799–806. [PubMed]
  • Horn RG, Fauci AS, Rosenthal AS, Wolff SM. Renal biopsy pathology in Wegener's granulomatosis. Am J Pathol. 1974 Mar;74(3):423–440. [PMC free article] [PubMed]
  • Germuth FG, Jr, Valdes AJ, Taylor JJ, Wise O, Rodriguez E. Fatal immune complex glomerulonephritis without deposits. Johns Hopkins Med J. 1975 May;136(5):189–192. [PubMed]
  • Stilmant MM, Bolton WK, Sturgill BC, Schmitt GW, Couser WG. Crescentic glomerulonephritis without immune deposits: clinicopathologic features. Kidney Int. 1979 Feb;15(2):184–195. [PubMed]
  • Ronco P, Verroust P, Mignon F, Kourilsky O, Vanhille P, Meyrier A, Mery JP, Morel-Maroger L. Immunopathological studies of polyarteritis nodosa and Wegener's granulomatosis: a report of 43 patients with 51 renal biopsies. Q J Med. 1983 Spring;52(206):212–223. [PubMed]
  • GODMAN GC, CHURG J. Wegener's granulomatosis: pathology and review of the literature. AMA Arch Pathol. 1954 Dec;58(6):533–553. [PubMed]
  • Bhathena DB, Migdal SD, Julian BA, McMorrow RG, Baehler RW. Morphologic and immunohistochemical observations in granulomatous glomerulonephritis. Am J Pathol. 1987 Mar;126(3):581–591. [PMC free article] [PubMed]
  • Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4115–4119. [PMC free article] [PubMed]
  • Merrill DP. Purification of human myeloperoxidase by Concanavalin A-Sepharose affinity chromatography. Prep Biochem. 1980;10(2):133–50. [PubMed]
  • Klebanoff SJ, Waltersdorph AM, Rosen H. Antimicrobial activity of myeloperoxidase. Methods Enzymol. 1984;105:399–403. [PubMed]
  • Hoyer JR, Mauer SM, Michael AF. Unilateral renal disease in the rat. I. Clinical, morphologic, and glomerular mesangial functional features of the experimental model produced by renal perfusion with aminonucleoside. J Lab Clin Med. 1975 May;85(5):756–768. [PubMed]
  • Johnson RJ, Guggenheim SJ, Klebanoff SJ, Ochi RF, Wass A, Baker P, Schulze M, Couser WG. Morphologic correlates of glomerular oxidant injury induced by the myeloperoxidase-hydrogen peroxide-halide system of the neutrophil. Lab Invest. 1988 Mar;58(3):294–301. [PubMed]
  • Pryzwansky KB, Martin LE, Spitznagel JK. Immunocytochemical localization of myeloperoxidase, lactoferrin, lysozyme and neutral proteases in human monocytes and neutrophilic granulocytes. J Reticuloendothel Soc. 1978 Sep;24(3):295–310. [PubMed]
  • Tervaert JW, Goldschmeding R, Elema JD, Limburg PC, van der Giessen M, Huitema MG, Koolen MI, Hené RJ, The TH, van der Hem GK, et al. Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum. 1990 Aug;33(8):1264–1272. [PubMed]
  • Pinching AJ, Rees AJ, Pussell BA, Lockwood CM, Mitchison RS, Peters DK. Relapses in Wegener's granulomatosis: the role of infection. Br Med J. 1980 Sep 27;281(6244):836–838. [PMC free article] [PubMed]
  • Johnson RJ, Couser WG, Chi EY, Adler S, Klebanoff SJ. New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. J Clin Invest. 1987 May;79(5):1379–1387. [PMC free article] [PubMed]
  • Klebanoff SJ. Oxygen metabolism and the toxic properties of phagocytes. Ann Intern Med. 1980 Sep;93(3):480–489. [PubMed]
  • Henson PM, Johnston RB., Jr Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest. 1987 Mar;79(3):669–674. [PMC free article] [PubMed]
  • Fleuren G, Grond J, Hoedemaeker PJ. In situ formation of subepithelial glomerular immune complexes in passive serum sickness. Kidney Int. 1980 May;17(5):631–637. [PubMed]
  • Weiss SJ. Tissue destruction by neutrophils. N Engl J Med. 1989 Feb 9;320(6):365–376. [PubMed]
  • Dijkstra CD, Döpp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...