• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Nov 1, 1997; 100(9): 2303–2309.
PMCID: PMC508426

Pathogenic antibodies inhibit the binding of apolipoproteins to megalin/gp330 in passive Heymann nephritis.

Abstract

Megalin/gp330 is an endocytic receptor that internalizes multiple ligands including apolipoproteins E (apo E) and B100 (apo B). Megalin is the main antigenic target in passive Heymann nephritis (pHN), where it binds circulating autoantibodies leading to the formation of subepithelial immune deposits (ID)-the hallmark of pHN. Apo E and apo B were found recently to accumulate within these IDs, and evidence was provided that their lipids may undergo peroxidation, causing glomerular basement membrane damage and proteinuria. Here we investigated if ID-forming antimegalin IgG can inhibit the binding and internalization of apo E-betaVLDL (very low density lipoprotein) by megalin, and lead to their accumulation within IDs. By immunoelectron microscopy, apo E and apo B were detected in clathrin-coated pits and multivesicular bodies of podocytes in control rats, suggesting that the uptake of lipoproteins is a constitutive function of the glomerular epithelium. When pHN was induced by intravenous injection of antimegalin IgG, apo E and apo B were found within IDs by immunofluorescence and immunoelectron microscopy. Bound antibodies eluted from glomeruli of rats with pHN were found to inhibit the binding and internalization of apo E-enriched betaVLDL by megalin. These results indicate that pHN-inducing antimegalin IgG is capable of interfering with the uptake of lipoproteins by megalin in vivo during the formation of IDs.

Full Text

The Full Text of this article is available as a PDF (573K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Schlöndorff D, Dendorfer U, Brumberger V, Keuneke C. Limitations of therapeutic approaches to glomerular diseases. Kidney Int Suppl. 1995 Aug;50:S19–S25. [PubMed]
  • HEYMANN W, HACKEL DB, HARWOOD S, WILSON SG, HUNTER JL. Production of nephrotic syndrome in rats by Freund's adjuvants and rat kidney suspensions. Proc Soc Exp Biol Med. 1959 Apr;100(4):660–664. [PubMed]
  • Cavallo T. Membranous nephropathy. Insights from Heymann nephritis. Am J Pathol. 1994 Apr;144(4):651–658. [PMC free article] [PubMed]
  • Kerjaschki D, Neale TJ. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis) J Am Soc Nephrol. 1996 Dec;7(12):2518–2526. [PubMed]
  • Farquhar MG, Kerjaschki D, Lundstrom M, Orlando RA. gp330 and RAP: the Heymann nephritis antigenic complex. Ann N Y Acad Sci. 1994 Sep 10;737:96–113. [PubMed]
  • Saito A, Pietromonaco S, Loo AK, Farquhar MG. Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9725–9729. [PMC free article] [PubMed]
  • Raychowdhury R, Niles JL, McCluskey RT, Smith JA. Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor. Science. 1989 Jun 9;244(4909):1163–1165. [PubMed]
  • Stefansson S, Chappell DA, Argraves KM, Strickland DK, Argraves WS. Glycoprotein 330/low density lipoprotein receptor-related protein-2 mediates endocytosis of low density lipoproteins via interaction with apolipoprotein B100. J Biol Chem. 1995 Aug 18;270(33):19417–19421. [PubMed]
  • Willnow TE, Goldstein JL, Orth K, Brown MS, Herz J. Low density lipoprotein receptor-related protein and gp330 bind similar ligands, including plasminogen activator-inhibitor complexes and lactoferrin, an inhibitor of chylomicron remnant clearance. J Biol Chem. 1992 Dec 25;267(36):26172–26180. [PubMed]
  • Exner M, Susani M, Witztum JL, Hovorka A, Curtiss LK, Spitzauer S, Kerjaschki D. Lipoproteins accumulate in immune deposits and are modified by lipid peroxidation in passive Heymann nephritis. Am J Pathol. 1996 Oct;149(4):1313–1320. [PMC free article] [PubMed]
  • Neale TJ, Ojha PP, Exner M, Poczewski H, Rüger B, Witztum JL, Davis P, Kerjaschki D. Proteinuria in passive Heymann nephritis is associated with lipid peroxidation and formation of adducts on type IV collagen. J Clin Invest. 1994 Oct;94(4):1577–1584. [PMC free article] [PubMed]
  • Orlando RA, Farquhar MG. Identification of a cell line that expresses a cell surface and a soluble form of the gp330/receptor-associated protein (RAP) Heymann nephritis antigenic complex. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4082–4086. [PMC free article] [PubMed]
  • Saito A, Yamazaki H, Rader K, Nakatani A, Ullrich R, Kerjaschki D, Orlando RA, Farquhar MG. Mapping rat megalin: the second cluster of ligand binding repeats contains a 46-amino acid pathogenic epitope involved in the formation of immune deposits in Heymann nephritis. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8601–8605. [PMC free article] [PubMed]
  • Kerjaschki D, Farquhar MG. 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. [PMC free article] [PubMed]
  • Miettinen A, Dekan G, Farquhar MG. Monoclonal antibodies against membrane proteins of the rat glomerulus. Immunochemical specificity and immunofluorescence distribution of the antigens. Am J Pathol. 1990 Oct;137(4):929–944. [PMC free article] [PubMed]
  • Orlando RA, Kerjaschki D, Kurihara H, Biemesderfer D, Farquhar MG. gp330 associates with a 44-kDa protein in the rat kidney to form the Heymann nephritis antigenic complex. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6698–6702. [PMC free article] [PubMed]
  • Kerjaschki D, Farquhar MG. 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. [PMC free article] [PubMed]
  • Orlando RA, Kerjaschki D, Farquhar MG. Megalin (gp330) possesses an antigenic epitope capable of inducing passive Heymann nephritis independent of the nephritogenic epitope in receptor-associated protein. J Am Soc Nephrol. 1995 Jul;6(1):61–67. [PubMed]
  • Horvat R, Hovorka A, Dekan G, Poczewski H, Kerjaschki D. Endothelial cell membranes contain podocalyxin--the major sialoprotein of visceral glomerular epithelial cells. J Cell Biol. 1986 Feb;102(2):484–491. [PMC free article] [PubMed]
  • Lundstrom M, Orlando RA, Saedi MS, Woodward L, Kurihara H, Farquhar MG. Immunocytochemical and biochemical characterization of the Heymann nephritis antigenic complex in rat L2 yolk sac cells. Am J Pathol. 1993 Nov;143(5):1423–1435. [PMC free article] [PubMed]
  • Susani M, Schulze M, Exner M, Kerjaschki D. Antibodies to glycolipids activate complement and promote proteinuria in passive Heymann nephritis. Am J Pathol. 1994 Apr;144(4):807–819. [PMC free article] [PubMed]
  • Kerjaschki D, Miettinen A, Farquhar MG. Initial events in the formation of immune deposits in passive Heymann nephritis. gp330-anti-gp330 immune complexes form in epithelial coated pits and rapidly become attached to the glomerular basement membrane. J Exp Med. 1987 Jul 1;166(1):109–128. [PMC free article] [PubMed]
  • Farquhar MG, Saito A, Kerjaschki D, Orlando RA. The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol. 1995 Jul;6(1):35–47. [PubMed]
  • Orlando RA, Farquhar MG. Functional domains of the receptor-associated protein (RAP). Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3161–3165. [PMC free article] [PubMed]
  • Czekay RP, Orlando RA, Woodward L, Lundstrom M, Farquhar MG. Endocytic trafficking of megalin/RAP complexes: dissociation of the complexes in late endosomes. Mol Biol Cell. 1997 Mar;8(3):517–532. [PMC free article] [PubMed]
  • Couser WG. Mechanisms of glomerular injury in immune-complex disease. Kidney Int. 1985 Sep;28(3):569–583. [PubMed]
  • Kerjaschki D, Schulze M, Binder S, Kain R, Ojha PP, Susani M, Horvat R, Baker PJ, Couser WG. Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. J Immunol. 1989 Jul 15;143(2):546–552. [PubMed]
  • Shah SV. Role of reactive oxygen metabolites in experimental glomerular disease. Kidney Int. 1989 May;35(5):1093–1106. [PubMed]
  • Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet. 1994 Sep 17;344(8925):793–795. [PubMed]
  • Raychowdhury R, Zheng G, Brown D, McCluskey RT. Induction of Heymann nephritis with a gp330/megalin fusion protein. Am J Pathol. 1996 May;148(5):1613–1623. [PMC free article] [PubMed]
  • Orlando RA, Exner M, Czekay RP, Yamazaki H, Saito A, Ullrich R, Kerjaschki D, Farquhar MG. Identification of the second cluster of ligand-binding repeats in megalin as a site for receptor-ligand interactions. Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2368–2373. [PMC free article] [PubMed]
  • Edgington TS, Glassock RJ, Dixon FJ. Autologous immune-complex pathogenesis of experimental allergic glomerulonephritis. Science. 1967 Mar 17;155(3768):1432–1434. [PubMed]
  • Miettinen A, Törnroth T, Tikkanen I, Virtanen I, Linder E. Heymann nephritis induced by kidney brush border glycoproteins. Lab Invest. 1980 Dec;43(6):547–555. [PubMed]
  • Tsai WM, Roos G, Hugli TE, Tan EM. Influence of free thiol group(s) on autoantibody-defined epitope of proliferating cell nuclear antigen. J Immunol. 1992 Sep 15;149(6):2227–2233. [PubMed]
  • Sato H, Suzuki S, Kobayashi H, Ogino S, Inomata A, Arakawa M. Immunohistological localization of apolipoproteins in the glomeruli in renal disease: specifically apoB and apoE. Clin Nephrol. 1991 Sep;36(3):127–133. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

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