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Query: UMLS:C0033687 (proteinuria)
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The Authors discuss the etiologic, pathogenetic and immunopathologic aspects of Heymann nephritis, in order to compare the numerous acquisitions concerning this nephropathy with the scanty knowledge of human membranous nephropathy, of which it represents the experimental counterpart. This rat disease can be obtained by inoculation of tubular brush border preparations (active form) or of the relevant antibodies (passive form); after an initial hypothesis of glomerular deposition of circulating immune complexes, studies on its pathogenetic mechanisms, instead demonstrated that in situ immunoaggregates, caused by an interaction between circulating antibodies and fixed glomerular antigens, are formed. Recent investigations have led to the identification of a major nephritogenic antigen (gp330), which is a tubular brush border glycoprotein expressed by coated pits located at the glomerular epithelial cell surface. Studies on antigen-antibody interactions at this level have demonstrated that there is a quick redistribution and accumulation of the so-formed immune complexes, and when polyclonal antibodies were utilized, growth of subepithelial electron dense deposits was observed. Although other tubulo-glomerular antigens, which can also be expressed by endothelial cells, play an uncertain role, they seem to favour transmembrane passing of anti-gp330 antibodies. Immune complex formation gives rise to the onset of proteinuria through complement system activation, without leukocyte involvement: in particular a MAC and C9 fraction lytic effect was demonstrated on cultured epithelial cells. In conclusion, studies on Heymann nephritis contribute to our understanding of the etiopathogenetic mechanisms regarding human membranous nephropathy, and emphasize a possible role played by tubular antigens and in situ formed immune complexes.
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PMID:[Etiopathogenesis of membranous nephropathy: is there a correlation between experimental and human pathology?]. 248 93

Advances in biomedical technology have contributed effectively to the resolution of basic and clinical problems in Nephrology. Most of our insights on glomerular diseases come from animal models. Antibodies against components of the extracellular matrix have been shown to induce glomerular changes in vivo and the non-collagenous NC1 domain of type IV collagen has been demonstrated to contain the Goodpasture antigen. New pathogenetic mechanisms of glomerular injury are suggested by studies on the interaction of antibodies with glomerular cell surface antigens. Gp330, a glycoprotein expressed at the surface of glomerular visceral epithelial cells, has been recognized to be the most relevant antigen of Heymann nephritis. Antibodies able to crosslink gp330 bind to the antigen at the base of foot processes and the resulting immune complexes are shed into the subepithelial space where they form electron dense deposits. The complement membrane attack complex (C5b-9) is likely to be directly responsible for epithelial cell injury and proteinuria in this model. Other cell surface antigens of the glomerular capillary wall, such as dipeptidyl dipeptidase IV, podocalyxin, podoendin, have been characterized. A novel model of glomerular injury comes from the demonstration that a non-complement fixing monoclonal antibody to a surface sialo-glycoprotein (SGP-115/107) binds to glomerular visceral epithelial cells and causes morphological changes which appear epitope-specific and complement and leukocyte-independent. The mechanisms responsible for the progression of renal disease to glomerular sclerosis have been extensively explored in the last years. Among the hemodynamic factors intraglomerular hypertension has been established to play an important part, at least in some models.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Nephrology]. 269 52

Deposition of the C5b-9 complex of C in glomeruli of rats with experimental membranous nephropathy (MN) is essential for the development of proteinuria. In this investigation C5b-9 was localized in the passive Heymann nephritis (PHN) by immunoelectron microscopy with a mAb specific for C5b-9(m) neoantigen. Its distribution was compared with that in another model of MN induced by successive injections of cationic human IgG and rabbit anti-human IgG into rats. In PHN C5b-9 was found: 1) in the immune deposits (ID), and on the cell membranes of foot processes close to the ID; 2) in clathrin-coated pits of the glomerular epithelial cells (GEC) close to the ID and in membrane vesicles in the cytoplasm, separated from sheep IgG and the gp330 Ag; 3) in high concentration in multivesicular bodies of GEC; and 4) in association with membrane vesicles in the urinary space which presumably are the exocytosed content of membrane vesicular bodies. By contrast, in the cationic IgG-MN model C5b-9 was found mostly in ID, but rarely within the GEC. By freeze-fracture electron microscopy we have further identified 200- to 250-A intramembrane particles in PHN in the cell membranes of the "soles" of the foot processes which resemble membrane inserted human C5b-9(m). Degradation products of C5b-9 were further detected by immunoblotting of a 100,000 x g pellet of PHN rat urine. These results indicate that, in PHN, C5b-9 is inserted into the cell membranes of GEC, and that it is selectively endocytosed and transported across GEC by a cellular mechanism which apparently protects the cell from accumulation of membrane-inserted C5b-9.
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PMID:Transcellular transport and membrane insertion of the C5b-9 membrane attack complex of complement by glomerular epithelial cells in experimental membranous nephropathy. 273 3

Antibodies specific for the core protein of basement membrane HSPG (Mr = 130,000) were administered to rats by intravenous injection, and the pathologic consequences on the kidney were determined at 3 min to 2 mo postinjection. Controls were given antibodies against gp330 (the pathogenic antigen of Heymann nephritis) or normal rabbit IgG. The injected anti-HSPG(GBM) IgG disappeared rapidly (by 1 d) from the circulation. The urinary excretion of albumin increased in a dose-dependent manner during the first 4 d, was increased 10-fold at 1-2 mo, but remained moderate (mean = 12 mg/24 h). By immunofluorescence the anti-HSPG(GBM) was seen to bind rapidly (by 3 min) to all glomerular capillaries, and by immunoperoxidase staining the anti-HSPG was seen to bind exclusively to the laminae rarae of the GBM where it remained during the entire 2-mo observation period. C3 was detected in glomeruli immediately after the injection (3 min), where it bound exclusively to the lamina rara interna; the amount of C3 bound increased up to 2 h but decreased rapidly thereafter, and was not detectable after 4 d. Mononuclear and PMN leukocytes accumulated in glomerular capillaries, adhered to the capillary wall, and extended pseudopodia through the endothelial fenestrae to contact in the LRI of the GBM where the immune deposits and C3 were located. At 1 wk postinjection, staining for C3 reappeared in the glomeruli of some of the rats, and by this time most of the rats, including controls injected with normal rabbit IgG, had circulating anti-rabbit IgG (by ELISA) and linear deposits of rat IgG along the GBM (by immunofluorescence). Beginning at 9 d, there was progressive subepithelial thickening of the GBM which in some places was two to three times its normal width. This thickening was due to the laying down of a new layer of basement membrane-like material on the epithelial side of the GBM, which gradually displaced the old basement membrane layers toward the endothelium. The results show that the core proteins of this population of basement membrane HSPG (Mr = 130,000), which are ubiquitous components of basement membranes, are exposed to the circulation and can bind anti-HSPG(GBM) IgG in the laminae rarae of the GBM. Binding of these antibodies to the GBM leads to changes (C3 deposition, leukocyte adherence, moderate proteinuria, GBM thickening) considered typical of the acute phase of anti-GBM glomerulonephritis. Antibody binding interferes with the normal turnover of the GBM, presumably by affecting the biosynthesis and/or degradation of basement membrane components.
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PMID:Antibodies to basement membrane heparan sulfate proteoglycans bind to the laminae rarae of the glomerular basement membrane (GBM) and induce subepithelial GBM thickening. 293 68

Heymann nephritis (HN) is an experimentally induced glomerulonephropathy of the rat characterized by subepithelial immune deposits and proteinuria. Immunization with a complex multimeric glycoprotein, gp600, comprising four subunits gp330, gp140, gp110, and gp70 has been shown to induce the complete form of the disease including proteinuria. Examination of three different batches of heterologous anti-gp600 antisera by immunoblot technique showed that the reactivity toward gp70 was dominant and common to all three antisera. gp70 was isolated from Triton X-100-solubilized Fx1A by lectin Lens culinaris affinity chromatography, and the purity was confirmed by SDS-PAGE. Ten rats were actively immunized with 200 micrograms of gp70. All 10 animals developed circulating brush border antibody and typical granular IgG deposits in the glomerulus but only 1/10 animals developed abnormal proteinuria. A potent antiserum against gp70 was prepared in the rabbit. It reacted strongly to the glomerular capillary wall and the proximal tubular brush border by immunofluorescence. By Protein A immunogold technique using anti-gp70, gold particles were found associated with the glomerular basement membrane (GBM)-endothelial region. By immunoblot analysis of rat GBM using the same anti-gp70 antiserum, a 70-kDa cross-reactive antigen was demonstrated in GBM preparations. These results show that the smallest subunit, gp70 of the complete HN antigen, gp600/Fx1A can independently induce the lesion of HN, but without proteinuria. The presence of gp70 on the endothelial side of the GBM is consistent with a role for in situ antigen-antibody reactions at sites other than the subepithelial region in the pathogenesis of HN.
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PMID:Nephritogenicity and immunocytochemical localization of the 70-kilodalton glycoprotein subunit (gp70) of Heymann antigen. 328 3

Passive Heymann nephritis (PHN) is an animal model of immune-complex-induced renal disease resembling human membranous glomerulonephritis. It was induced in rats by injecting rabbit antiserum directed against glycoprotein antigens isolated from rat embryonic visceral yolk-sac microvilli (VYS-MV). The glycoprotein antigens were isolated by extracting the VYS-MV with detergent Nonidet P-40 followed by gel filtration in Sephacryl S-300 and finally by lectin affinity chromatography with Ricinus communis agglutinin I. In vitro immunofluorescent localization studies demonstrated that the nephritogenic antibodies were localized along the apical region of the visceral yolk-sac endodermal cells and the brush border of the proximal tubular cells of the kidney. Rats injected with a single dose of the antiserum manifested proteinuria. Indirect immunofluorescent studies showed that the injected rabbit IgG was localized in vivo along the capillary walls of the glomerulus in a granular fashion. Electron microscopic examination of the same kidney glomeruli revealed numerous electron-dense deposits along the lamina rara externa of the glomerular basement membrane. Fusion of the epithelial foot processes was also present. These findings represent the typical immunopathological characteristics of Heymann nephritis. Furthermore, with the aid of Ouchterlony analysis, the antiserum against the isolated VYS antigens exhibited an immunoprecipitin band which was in common with that formed by the antiserum against the homogeneous nephritogenic antigen (gp330) of renal brush border origin. Thus, the nephritogenic antigens which have been found to be associated with the brush border of the renal proximal tubules may also be present or cross-reacted in the microvilli of the rat embryonic visceral yolk-sac.
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PMID:Passive Heymann nephritis induced by rabbit antiserum to membrane antigens isolated from rat visceral yolk-sac microvilli. 330 94

Passive Heymann nephritis with acute and severe proteinuria was produced in rats by a single injection of heterologous antibody against a purified glycoprotein which consisted of homologous subunits with a molecular weight of 108,000 (gp108). Gp108 was identified as one of the major antigens in rat renal tubular fraction (FX1A) on immunoblotting assay by using total proteins of FX1A and rabbit antiserum against FX1A. A band of gp330, which was identified as a pathogenic antigen of Heymann nephritis by Kerjaschki D and Farquhar MG (Proc Natl Acad Sci USA 79:5557, 1982) was detected as another band by Coomassie blue staining and immunoblotting. Autoantibodies in the sera of FX1A-injected (active Heymann nephritis) rats reacted to the band of gp330 but not to gp108. These results indicate that gp108 is a different glycoprotein from both gp330 and its degradation products. GP108 was subsequently purified to near homogeneity by extraction with Triton X-100, and then DEAE-cellulose and Bio-Gel A-1.5m column chromatographies. On gel permeation chromatography, the purified antigen showed a molecular weight of 310,000, suggesting that it consists of dimer or trimer of gp108. Rabbits immunized with gp108 produced an antibody which showed monospecific binding to gp108. The antibody stained with brush border of proximal renal tubules in addition to the capillary loops in rat glomeruli by indirect immunofluorescence. Injection of rabbit antiserum against gp108 in rats induced severe proteinuria within 2 days. On the 2nd day after the injection, the glomeruli of the animals showed granular immune deposits along the capillary loops in addition to dominant staining of the brush border of the proximal tubules by immunofluorescence. These results indicate that gp108 is a pathogenic antigen in passive Heymann nephritis and that an antibody against gp108 has a nephritogenic and proteinuria-inducing activity.
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PMID:Passive Heymann nephritis with acute and severe proteinuria induced by heterologous antibody against renal tubular brush border glycoprotein gp108. 375 92

Monoclonal autoantibodies were obtained from Lewis rats with active Heymann nephritis. Two cloned rat/mouse hybridomas, 3D9B and 5B8C, that secreted rat IgG2a autoantibodies were selected for their ability to react with gp330 in ELISA and propagated further. Their specificity was confirmed by immunoprecipitation of crude antigens from a yolk sac carcinoma cell line expressing gp330. The size of the precipitated molecule was identical to that immunoprecipitated by previously described anti-gp330 antibodies. Indirect immuno-electron microscopy showed that 3D9B exclusively stained the intermicrovillous areas of the tubular brush border membrane, while 5B8C stained the full tubular microvillous membrane and the glomerular epithelial coated pits. Passive transfer of 3D9B did not induce Ig deposits or functional renal damage within 7 days. However, injection of 5B8C caused granular glomerular deposits within 1 h, subepithelial immune aggregates within 6 days and antibody deposition on the brush border within 7 days. Only ascites production of clone 5B8C in rats, but not in mice, caused subepithelial immune deposits and abnormal proteinuria. This study shows that a single monoclonal autoantibody to gp330 is able to induce a mild form of Heymann nephritis.
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PMID:Glomerulopathy induced by a single monoclonal autoantibody against GP330. 762 90

In active Heymann nephritis, an experimental autoimmune disease in the rat, gp330 is regarded as the main antigenic target. Immunization with detergent-solubilized renal tubular epithelium (RTE-DOC) has been shown to be less nephritogenic than immunization with crude RTE. In this study immunization with either crude RTE or affinity-purified gp330 did, but immunization with RTE-DOC did not induce proteinuria. Both a possible aberrant subclass distribution of anti-gp330 autoantibodies and the involvement of additional nephritogenic autoantigens such as DPP IV (gp90) or laminin could be excluded. Circulating anti-gp330 autoantibody titers were significantly higher in RTE-DOC-immunized rats than in RTE-immunized animals. In contrast, significantly more antibodies were shown to bind in the glomeruli in the latter group. The time of onset of abnormal proteinuria was shown to be related to the recognition of a particular V8 protease-induced 250 kD fragment of gp330 in Western blots. This study shows that a particular fragment-specific subset of autoantibodies against gp330 is involved in the glomerular damage in Heymann nephritis.
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PMID:Epitope specificity of anti-gp330 autoantibodies determines the development of proteinuria in active Heymann nephritis. 768 Dec 58

Passive Heymann nephritis (PHN) in the rat is induced by the administration of heterologous antibodies to renal tubular epithelium (RTE). The nephritogenic capacity of anti-RTE resides primarily in the antibody fraction directed against a 330-kD glycoprotein (gp330). However, monospecific anti-gp330 antibodies are less nephritogenic than anti-RTE antibodies. This discrepancy led us to study a possible synergizing role for different antibody specificities present within anti-RTE. The enzyme dipeptidyl peptidase type IV (DPP IV) is, like gp330, present in RTE as well as in the glomerulus. Anti-DPP IV antibodies have been shown to induce an acute, transient proteinuria. In this study, we investigated the nephritogenic effect of separate or simultaneous administration of heterologous anti-DPP IV and anti-gp330 antibodies. Injection of anti-DPP IV antibodies resulted in a short-lived glomerular binding, and in a dose-dependent polyuria, albuminuria or proteinuria. Binding of anti-gp330 antibodies was slower, but much more stable. Albuminuria could only be observed in the heterologous phase. Combined injection did not alter antibody-binding kinetics of either antibody nor the albuminuria induced by anti-gp330. However, in the presence of anti-gp330 antibodies, a lower dose of anti-DPP IV was capable to induce transient albuminuria as compared to anti-DPP IV alone. In conclusion, anti-DPP IV and anti-gp330 antibodies bind to different sites in the glomerulus with different kinetics. The presence of anti-gp330 deposits facilitated anti-DPP-IV-induced renal injury.
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PMID:Synergistic effects of anti-gp330 and anti-dipeptidyl peptidase type IV antibodies in the induction of glomerular damage. 791 60


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