Determinants of glomerular localization of subepithelial immune deposits: effects of altered antigen to antibody ratio, steroids, vasoactive amine antagonists, and aminonucleoside of puromycin on passive Heymann nephritis in rats.

The role of circulating immune complex deposition versus in situ complex formation in membranous nephropathy is controversial. Passive Heymann nephritis in rats resembles membranous nephropathy in man and was induced by injection of sheep antibody to rat proximal tubular epithelial cell brush border antigen (anti-Fx1A). Minutes after injection of 1 ml. of anti-Fx1A, subepithelial immune deposits were seen by immunofluorescence and electron microscopy, and proteinuria appeared within 5 days. The effects of alterations in the dose of administered antibody, corticosteroid therapy, and vasoactive amine blockade on the development of subepithelial deposits and consequent proteinura were studied. Variation of the dose of anti-Fx1A from 0.25 ml. to 1 ml. resulted in a progressive increase in the size and number of glomerular capillary wall deposits, but no alterations in their distribution. Only those rats which received 1 ml. became proteinuric within 5 days. Corticosteroid therapy and vasoactive amine blockade, begun 24 hours prior to the induction of passive Heymann nephritis and continued until termination of the study 5 days later, had no effect on the amount or site of immune complex formation, nor on the extent of proteinuria as compared to untreated controls. In contrast, in rats with unilateral proteinuria produced by the selective perfusion of one kidney with aminonucleoside of puromycin 7 days prior to the induction of passive Heymann nephritis, there was a marked reduction of subepithelial deposits in the perfused kidney as compared to the nonperfused contralateral kidney. In this model of membranous nephropathy, systemic factors play little role in the development of subepithelial deposits, whereas local factors are critical. These findings are consistent with the hypothesis that subepithelial immune deposits form locally.     

Strain variation in susceptibility to the development of monoclonal antibody 5-1-6-induced proteinuria in rats.

Susceptibility to the development of MoAb 5-1-6-induced proteinuria was investigated in four different rat strains, i.e. Brown-Norway (BN), Lewis (LEW), Sprague-Dawley (SD) and Wistar. An intravenous injection of 5 mg of MoAb 5-1-6 to female 7-week-old rats of a given strain induced massive proteinuria in BN, LEW and Wistar rats. However, SD rats developed almost no proteinuria. A similar tendency was observed in the second experiment, in which the injected dose of MoAb was adjusted according to the body weight of each rat (3 mg/100 g body weight). Immunofluorescence (IF) and immunoelectron microscopy (IEM) revealed no differences between the binding patterns of the MoAbs to normal rat kidneys derived from each strain. Quantitative study using 125I-labelled MoAb showed that there was no significant difference in the amount of antibody bound to the kidney 1 h and 5 days after injection between two rat strains, LEW and SD. Localization of 5-1-6 in vivo and its kinetics were investigated. In IF a linear-like pattern along capillary walls was observed 2 h after injection in both LEW and SD strains. This linear-like pattern was shifted to a granular pattern in proteinuric LEW rats 6 days after injection, whereas it remained linear-like in non-proteinuric SD rats. IEM confirmed this difference in the localization of injected MoAb 6 days after injection to LEW and SD rats also at the ultrastructural level. We conclude that there is a clear-cut strain difference in the development of proteinuria induced by MoAb 5-1-6. SD rats were less susceptible to MoAb-induced glomerular injury than BN, LEW and Wistar rats. Although the exact reason for strain variation in susceptibility to MoAb-induced proteinuria remains to be clarified, the movement of bound MoAb, presumably together with corresponding antigenic molecule along the glomerular epithelial cell surface followed by endocytosis into the epithelial cell, seems to be closely related to the induction of proteinuria.     

Quantitative studies of monoclonal antibody 5-1-6-induced proteinuric state in rats.

Murine monoclonal antibody (MoAb) 5-1-6 was already reported to bind to epithelial cell foot processes and to cause proteinuria in rats. In vivo kinetics of the injected MoAb 5-1-6, relationship between the quantity of kidney-binding antibody and proteinuria, and changes in the amount of antigenic molecule recognized by this MoAb in the proteinuric state were studied. The amount of total kidney-binding antibody (TKAb) as determined 1 h after a 2 mg administration was 50.8 +/- 10.4 micrograms/2 kidneys, and TKAb declined to 1.9 +/- 0.4 at day 15. The minimum dose of MoAb required to induce proteinuria was 125 micrograms as the injected dose. This dose corresponded to 12.8 micrograms of TKAb at 1 h and 0.34 micrograms of TKAb at day 5. The amount of MoAb 5-1-6 binding to isolated normal glomeruli was also shown to exceed 147.7 micrograms/76,000 glomeruli, indicating proteinuria to be induced provided more than 8.7% (= 12.8/147.7) of the critical epitopes is specifically occupied by MoAb. The total amount of MoAb 5-1-6 bound to glomeruli in vivo and in vitro was assayed with [125I]-labelled anti-mouse IgG. The amount of [125I] anti-mouse IgG bound to glomeruli was 6.93 +/- 0.45 micrograms/10,000 glomeruli from rat 5 days after this MoAb injection and 26.58 +/- 0.66 micrograms/10,000 control glomeruli, indicating the decrease in the number of MoAb 5-1-6-recognized antigen molecules in glomeruli isolated from the rat in proteinuric state induced by this MoAb. Thus, the MoAb 5-1-6-recognized molecule itself may principally function to regulate the permeability of the glomerular capillary wall and the decrease of the molecule may lead to proteinuria.     

Complement and monocytes are essential for provoking glomerular injury in passive Heymann nephritis in rats. Terminal complement components are not the sole mediators of proteinuria

Complement but not polymorphonuclear granulocytes (PMN) causes glomerular injury in passive Heymann nephritis in rats. We have now identified monocytes as another important mediator in this model. Passive Heymann nephritis was induced in Wistar rats by intravenous injection of sheep anti-rat Fx1A antiserum. Four groups (all receiving anti-rat Fx1A antiserum) were studied: (a) rats given normal sheep globulin (nephritic controls), (b) rats given sheep anti-rat PMN globulin (PMN-depleted), (c) rats given sheep anti-rat monocyte globulin (monocyte-depleted), (d) rats injected with cobra venom factor (complement-depleted). In vitro specificity controls for anti-cell antisera were made by cytotoxicity tests and inhibition of phagocytosis. In vivo specificity controls were performed in heterologous Masugi nephritis (PMN-dependent) and accelerated Masugi nephritis (monocyte-dependent). Complement and monocyte depletion significantly delayed the onset of proteinuria (p less than 0.001 versus nephritic controls on day 5), PMN depletion had no significant effect. Monocyte infiltration was seen in control nephritic rats, but monocyte depletion prevented this influx. In the monocyte-depleted group, no differences in glomerular deposition of C3, C9, and C5b-9 were seen in comparison to the nephritic control rats. Serum C3 levels were comparable in groups a, b, and c, the complement system was biologically active in the monocyte depleted-group (c), and the amount of anti-Fx1A antibody bound was the same in all groups. This shows that, besides complement, monocytes are required for induction of renal damage in passive Heymann nephritis. The concept of a sole role for complement in glomerular immune injury involving subepithelial immune deposits should be reconsidered.     

Effect of chlorpromazine on the development of experimental glomerulonephritis and Arthus reaction.

Chlorpromazine blocks antibody-mediated redistribution of cell surface antigens in vitro and in vivo and inhibits the development of passive Heymann glomerulonephritis, a disease characterized by in situ formation of immune complexes (Camussi et al J Immunol 1986, 136:2127-2135). The aim of this study was to establish whether chlorpromazine exerts similar effects in other rat models characterized by in situ formation of immune complexes. In glomerulonephritis induced by antibodies reactive with an exogenous antigen "planted" in glomeruli pretreatment with chlorpromazine prevented formation of "humps" and exudative and proliferative lesions. Likewise, chlorpromazine prevented passive reverse Arthus reaction in the skin. In contrast, the drug was ineffective when these lesions were already established, and also failed to inhibit the fulminant course of nephrotoxic serum glomerulonephritis with an enhanced autologous phase. It is proposed that the antiinflammatory effect of chlorpromazine is due to its ability to block the recruitment of inflammatory cells and the release of inflammatory mediators.     

Antibody-mediated proliferation of proximal tubule cells.

We have proposed that the deposition in vivo of anti-brush border antibodies on proximal tubule cells in Heymann nephritis stimulates those cells to divide. To evaluate that hypothesis, we have investigated the temporal relationship between antibody deposition and kidney cell proliferation, using autoradiography to detect dividing cells in rats with Heymann nephritis and in age-matched controls treated with Freund's adjuvant alone. To assess the possible stimulation of proximal tubule cell proliferation by factors associated with proteinuria and/or nephrotic syndrome, kidney cell proliferation was measured in rats with chronic serum sickness glomerulonephritis. Proteinuric rats with chronic serum sickness also served as recipients of anti-brush border antibodies in passive transfer experiments. Cell division rates were not altered by adjuvant treatment or ageing. In both active Heymann nephritis and passive transfer experiments, a highly elevated stimulation of 3H-thymidine incorporation, reflecting mitotic activity, was detected in the proximal tubule epithelium immediately following the deposition of antibodies on the brush border. Significant enhancement of cell division was not noted in other nephron segments. A much smaller increase in proximal tubule cell proliferation accompanied proteinuria in chronic serum sickness. A similar small elevation compared to controls was also detected in late stages of Heymann nephritis when the proximal tubules were free of immunoglobulin deposits. It appears that the reaction of divalent antibodies with plasma membrane antigens can produce proliferative pathology of the proximal tubule epithelium. Furthermore, a significant, if less dramatic, enhancement of cell proliferation may be secondary to proteinuria and/or other manifestations of the nephrotic syndrome.     

Antibodies to glycolipids activate complement and promote proteinuria in passive Heymann nephritis.

Passive Heymann nephritis is an experimental rat model of human membranous nephropathy induced by injection of antisera against crude renal cortical fractions such as Fx1A or rat tubular microvilli. This results in the formation of subepithelial immune deposits, the activation of the C5b-9 membrane attack complex of complement, and severe proteinuria. While the formation of immune deposits is attributed to in situ immune complex formation with antibodies specific for the gp330-Heymann nephritis antigenic complex (HNAC), activation of complement and proteinuria appear to be caused by at least one additional antibody species present in anti-Fx1A sera. We have separated by affinity absorption polyspecific antisera against Fx1A and rat microvilli into one IgG fraction directed specifically against microvillar proteins (anti-Fx1A-prot) and another IgG fraction specific for glycolipids (ant-Fx1A-lip) of tubular microvilli. When injected into rats, the anti-Fx1A-prot fraction induced immune deposits but failed to activate complement or produce proteinuria, similar to results obtained with affinity-purified anti-gp330 IgG. When the antibodies of the anti-Fx1A-lip fraction were injected alone they did not bind to glomeruli. By contrast, when the IgGs specific for the Fx1A-prot fraction (or for gp330-HNAC) were combined with those directed against the Fx1A-lip glycolipid preparation, immune deposits were formed, in situ complement activation was observed, and also proteinuria was induced. It is concluded that within anti-Fx1A and anti-microvillar sera there are at least two IgG fractions of relevance for the development of PHN: one directed against the gp330-HNAC complex which is responsible for the development of immune deposits, and a second specific for glycolipid antigen(s) which activate(s) the complement cascade.     

雷帕霉素减缓大鼠被动Heymann肾炎的进展

 目的：观察雷帕霉素对大鼠被动Heymann肾炎（PHN）的影响,并探讨自噬在其中的作用。方法：雄性SD大鼠随机分为3组,即对照组、PHN模型组和雷帕霉素治疗组。以造模后第21天为观察结点,采用全自动生化分析仪测定24 h尿蛋白总量、血尿素氮和血清肌酐,过碘酸-六次甲基四胺银染色观察肾脏病变,Weibel-Gomez点计数方法计数足细胞数量,免疫荧光染色检测肾小球内C5b-9的沉积,免疫组化染色观察caspase-3的表达,Western blotting检测肾小球LC3的表达。结果：雷帕霉素明显减轻PHN模型大鼠的蛋白尿排出（P<0.05）,同时各组大鼠的肾功能均正常,其间无显著差异;雷帕霉素使PHN大鼠肾小球基底膜增厚的程度和范围有所减轻;雷帕霉素明显改善PHN大鼠足细胞缺失情况,减少足细胞凋亡;雷帕霉素可增强肾小球内固有细胞的自噬水平。结论：在PHN的病变过程中,适度增强自噬减少足细胞凋亡,减轻肾脏病变和缓解蛋白尿,可能是雷帕霉素减缓大鼠PHN进展的重要机制之一。     

The effect of cyclosporin A on the interstitial mononuclear cell infiltration and the induction of Heymann''s nephritis.

Heymann's nephritis was induced with brush-border (BB) antigen. Interstitial mononuclear cell infiltration was studied with cytological examinations of fine-needle aspiration biopsies (FNAB), and with immunoperoxidase stains of frozen sections with monoclonal antisera. The effect of cyclosporin A (CyA), 20 mg/kg when administered intraperitoneally for 8 days in association with both initial immunization, and with the booster 4 weeks later, on the interstitial leukocyte infiltration and on the development of membranous glomerulonephritis (MGN) and proteinuria were investigated. Another group of rats was immunized, but not given CyA. Experimental animals were killed in groups 3, 6 and 20 weeks after initial immunization. CyA inhibited significantly the initial interstitial lymphocyte and blast cell response at 3 weeks (FNAB), but did not inhibit the secondary response after the booster. The anti-BB titre reacted in a similar fashion. Immunoperoxidase stains indicated a clearly suppressed T suppressor/cytolytic (T s/c) cell response. Glomerular basement membrane (GBM) deposits of IgG developed more slowly and were more scarce in the CyA-treated rats, when compared with the untreated group. Only one out of 15 CyA treated rats developed C3 deposits in the GBM during the course of the study, and none developed proteinuria, when most untreated rats (10/17) had C3 deposits and were nephrotic at 20 weeks. Thus, CyA depressed the initial interstitial cellular response after immunization with BB antigen, and also inhibited the development of antibody response, C3 deposits and proteinuria of Heymann nephritis. These effects of CyA may be contributed to an inhibited amplification of the autoimmune response associated with interstitial damage and continuous release of autoantigen.     

Tubular antigen-associated renal disease in New Zealand white rabbits.

Rabbits immunized with autologous renal tubular antigen (Fx1A) developed tubulointerstitial nephritis whereas sheep anti-Fx1A antibody administered i.v. produced glomerulonephritis (GN). This lesion showed heavy granular glomerular deposition of immunoglobulin and subepithelial electron dense deposits, early proteinuria, leucocyte independence and a temporal pattern of quantitated glomerular antibody binding distinct from that reported to occur in passive Heymann's nephritis in rats. Isoelectric focusing followed by immunoblotting of deoxycholate-soluble Fx1A antigens with the heterologous and autologous antibodies, indicated species differences in epitope recognition which could account for dissociation between the two models.     

Characterization of a polyreactive monoclonal antibody to dsDNA, F x 1A, and heparan sulfate generated from BALB/c mice immunized with rat renal homogenates

Monoclonal antibodies (MoAb) were prepared by fusing spleen cells from BALB/c mice immunized with rat renal cortical homogenates to the mouse myeloma cell. One of them, designated MoAb26-3, revealed a positive antinuclear activity by screening an indirect immunofluorescence test on kidney cryostat sections. The reactivity of MoAb26-3 with double-stranded deoxyribonucleic acid (dsDNA) was confirmed by the Crithidia luciliae assay. The isotype of MoAb26-3 was determined to be IgM-kappa. To test the nephritogenicity of MoAb26-3, the hybridomas were grafted intraperitoneally into BALB/c mice. A deposition of IgM was observed along the base of the epithelial foot processes and on the luminal surface of the endothelium by immunoelectron microscopy. By direct enzyme-linked immunosorbent assay (ELISA), MoAb26-3 was shown to react not only with dsDNA but also with fraction 1A of renal cortical supernatant (F x 1A) and heparan sulfate. On the basis of inhibition ELISA, the dsDNA inhibited F x 1A and heparan sulfate binding of MoAb26-3 and F x 1A blocked the reactivity of Mo26-3 with dsDNA and heparan sulfate, while heparan sulfate showed a less inhibition on the binding of MoAb26-3 with F x 1A, dsDNA, and even with heparan sulfate. Using immunoprecipitation with radiolabeled F x 1A, MoAb26-3 was shown to react with MW 330,000, 440,000, and 700,000 bands which were the same with those which polyclonal Heymann nephritis serum could react. An intravenous injection of MoAb26-3 to rats resulted in the deposition of IgM along the glomerular capillary wall, but resulted in an only transient appearance of proteinuria.     

Quantitative study of mesangial injury with proteinuria induced by monoclonal antibody 1-22-3.

Murine MoAb 1-22-3 has already been reported to bind to the mesangial cell surface and to cause transient proteinuria and mesangial morphological changes characterized by mesangiolysis, subsequent mesangial cell proliferation and mesangial matrix increase by a single i.v. injection. In this study, MoAb-induced glomerulopathy was quantitatively analysed. No correlation between the severity of mesangial morphological changes and the degree of proteinuria was detected (r = 0.190). The minimum dose injected to induce abnormal proteinuria was 25 micrograms. This dose corresponded to 1.79 micrograms/2 kidneys 30 min after MoAb injection. The highest average level of proteinuria was observed in rats injected with 500 micrograms of MoAb, and less proteinuria was observed in rats injected with 10.0, 5.0 and 2.0 mg. Although the amounts of kidney-fixing MoAb and the subsequent deposition of rat C3 in the high-dose-injected group were larger than in the 500 micrograms injected group, the numbers of infiltrating inflammatory cells were the same in both groups. No correlations between the degrees of such mediators and proteinuria were observed.     

The effects of a new immunosuppressive agent, FK506, on the glomerular injury in rats with accelerated nephrotoxic serum glomerulonephritis.

The aim of the present work was to study the effects of a new immunosuppressive drug, FK506, in accelerated nephrotoxic serum glomerulonephritis. Glomerulonephritis was induced in female Wistar rats by the preimmunization with normal rabbit IgG (Day-4) and the subsequent intravenous injection of rabbit anti-GBM serum (Day 0). Without treatment with FK506, rats developed proteinuria at Day 6 and onward. Rat anti-rabbit IgG was strongly detected at Day 6 and the titer was maintained through Day 20. Moderate hypercellularity and focal crescent formation were observed at Day 20. Rats injected intramuscularly with 0.3 or 1 mg/kg of FK506 did not develop proteinuria and the anti-rabbit IgG titer was much less or was undetectable throughout the experiments. These data suggest that FK506 is effective in the present model of glomerulonephritis.     

Cyclosporin A prevents proteinuria in an active model of membranous nephropathy in rats

The effect of the immunosuppressant Cyclosporin A on an active model of in situ immune complex glomerulonephritis was evaluated. Wistar rats were preimmunized with human IgG and 2 weeks after the last antigen injection, the left kidney was perfused with cationized human IgG in order to induce unilateral in situ immune complex glomerulonephritis. Three groups of rats were treated orally with Cyclosporin A (15 mg/kg body weight/day) beginning 2 days before induction of disease and continuing for 7 or 14 days afterwards, or alternatively treatment was commenced 5 days after induction of disease and continued until day 14. Cyclosporin A significantly reduced proteinuria (40 +/- 7 mg/day) in rats with immune complex glomerulonephritis when compared with untreated nephritic controls (250 +/- 65 mg/day). This effect was observed when rats were pretreated with Cyclosporin A and even when the drug was given in established disease, 5 days after induction. Proteinuria appeared in rats pretreated with Cyclosporin A when drug administration was stopped at day 7. Cyclosporin A did not alter immune complex formation in glomeruli or serum levels of anti-human-IgG antibody, nor did it reduce inulin clearance (CsA: 234 +/- 31 microliters/minute/100 gm body weight; controls: 119 +/- 27 microliters/minute/100 gm body weight). Morphologic studies did not reveal any differences between controls and the immunosuppressed rats. CsA failed to reduce proteinuria in the nonimmune mediated model of aminonucleoside nephrosis. The data demonstrate that Cyclosporin A can prevent the induction and more importantly ameliorate already established proteinuria in an autologous model of in situ immune complex glomerulonephritis. This latter finding is important since, in general, most treatment schedules have little, if any effect on established experimental glomerular disease.     

Induction of an Autologous Immune-complex Glomerulonephritis in the Rat by Intravenous Injection of Heterologous Anti-rat Kidney Tubular Antibody: I. Production of Chronic Progressive Immune-complex Glomerulonephritis

An autoimmune kidney disease morphologically and functionally similar to the Heymann autoimmune nephrosis can be produced in rats by the injection of BSA followed by heterologous anti-rat kidney tubular antibody. Animals injected with the anti-kidney tubular antibody only, developed a milder form of the typical renal lesion without proteinuria. Control animals injected with BSA or normal rabbit serum alone and BSA and normal rabbit serum together did not develop a progressive type of kidney disease.Gamma-globulin eluted from the developed lesions of the heterologous antibody induced glomerulonephritis was autologous IgG which reacted with the periluminal zone of the proximal tubules on normal rat kidney sections in a fluorescent antibody test. Gamma-globulin eluted from kidneys of homologous renal antigen induced autologous immune complex (AIC) nephritis reacted with normal rat kidney sections in a similar manner.It is suggested that heterologous anti-tubular antibody reaching the proximal convoluted tubules is reabsorbed and releases the nephritogenic antigen with subsequent formation of autoantibody to it. The continuous release of the nephritogenic antigen and the development of the chronic progressive autologous immune-complex glomerulonephritis is maintained by autoantibody produced as the result of the ongoing autoimmune processes.     

Downregulation of a pathogenic autoantibody response by IgM autoantibodies directed against the nephritogenic antigen in slowly progressive Heymann nephritis

The purpose of the study was to find out if a new modified vaccination technique would be effective in downregulating immunopathological events during the course of an experimental autoimmune kidney disease (which is morphologically and functionally similar to Heymann nephritis) called 'slowly progressive Heymann nephritis' (SPHN). We have shown that the pathogenic IgG autoantibody (aab)-induced experimental autoimmune kidney disease process can be downregulated early on as well as during the chronic progressive phase, when rats were restimulated. The IgM aab, resulting from stimulation by immune complexes made up of rat kidney fraction 3 (rKF3) antigen and rat anti-rKF3 IgM antibody in antigen excess (MIC), can greatly diminish pathogenic aab production by removing or blocking nephritogenic antigens. Reduced IgG aab production limits the formation of damaging immune complexes (IC) in the glomeruli and development of proteinuria. At the end of the experiment 60% and 80% of the MIC-treated groups had no pathogenic IgG aab in their circulation, while all the untreated SPHN rats had high levels of IgG aab associated with disease progression manifesting in increased proteinuria and severe immune complex glomerulonephritis.     

Differential capacity of anti-RAP and anti-megalin antibodies to produce progressive passive Heymann nephritis - implications for the pathogenesis of idiopathic human membranous glomerulonephritis

Passive Heymann nephritis (PHN) induced with heterologous antisera has been described according to various criteria, which may or may not include induction of chronic disease and proteinuria. Characteristics of the glomerular immune deposits determined by the antigenic specificities of the antisera presumably account for differences in disease outcome. In this study, the clinical and immunohistological features in the model produced with monospecific antisera were compared against megalin or receptor associated protein (RAP), two proteins that have been implicated as target antigens in PHN. Rats injected with either anti-megalin or anti-RAP antiserum developed typical glomerular immune deposits of PHN when examined after 7 days. Although the deposits stained for complement, none of the animals had abnormal proteinuria in this time frame. Over a longer time course (7-16 weeks), immune deposits persisted and proteinuria increased to pathological levels in all animals injected with anti-megalin serum. By contrast, immune deposits had cleared from the kidneys of rats injected with anti-RAP antiserum when examined at 7-8 weeks post-injection and the proteinuria levels observed up to 13 weeks remained in the normal range. Additional doses of anti-RAP antiserum given 4 and 17 days after the first injection did not prolong the duration of glomerular immune deposits. These results demonstrate a clear divergence in pathogenic potential of antisera generated against the two renal antigens, which suggest differences in the immune deposits linked to a soluble antigen that is non-covalently bound to the podocyte membrane versus those linked to an integral membrane antigen. These observations could provide clues to the nature of the unknown glomerular autoantigen of idiopathic membranous glomerulonephritis in humans.     

An evaluation of the role of complement depletion in experimental membranous nephropathy in the rat

Passive Heymann nephritis (PHN), a model of experimental membranous nephropathy produced by the administration of anti-Fx1A antibody, was studied by micropuncture measurement of glomerular hemodynamics and by assessment of immunologic and morphologic findings. The effect of complement depletion on these parameters was evaluated by administering cobra venom factor. Five days after administration of anti-Fx1A Ab to PHN controls, abnormal proteinuria developed and nephron filtration rate decreased due to modest reductions in nephron plasma flow and major reductions (75%) in the glomerular ultrafiltration coefficient. Glomerular capillary hydrostatic pressure gradient was significantly increased and decreased tubular reabsorption was also evident. Complement depletion prevented abnormal proteinuria and normalized tubular reabsorption and some of the glomerular hemodynamic parameters (nephron plasma flow and glomerular capillary hydrostatic pressure gradient). Values for the glomerular ultrafiltration coefficient, a possible index of membrane damage, were significantly improved (100%) after cobra venom factor treatment, although they remained below normal values. Only minimal differences in glomerular and epithelial cell morphology and appearance of electron-dense material were noted between PHN and PHN + cobra venom factor. These data suggest therefore that both complement-dependent and independent mechanisms contribute to explain the changes in nephron filtration and reabsorption that occur in this model of experimental membranous nephropathy.     

Down-regulation of pathogenic autoantibody response in a slowly progressive Heymann nephritis kidney disease model

In the present article, we describe an antigen-specific down-regulation of a pathogenic autoantibody (aab)-mediated disease process in an experimental autoimmune kidney disease in rats called slowly progressive Heymann nephritis (SPHN). This autoimmune disease is initiated and maintained by pathogenic immunoglobulin G (IgG) autoantibodies (aabs), which cause an immune-complex (IC) glomerulonephritis associated with proteinuria. We achieved down-regulated pathogenic aab response in SPHN rats by injections of an IC containing the native nephritogenic antigen and specific high-titred nonpathogenic IgM aabs, in antigen excess. The injected IC increased the level of circulating nonpathogenic IgM aabs; the increased levels of specific IgM aabs in turn facilitated the removal of the injected altered nephritogenic and liberated autoantigens from the renal tubules and greatly diminished the production of pathogenic aabs and the build up of immune deposits in the glomeruli. While animals treated early had advantages over rats whose kidney disease was well established before treatment; animals treated late into the disease still manifested noticeable improvements in similar areas, i.e. with lessened proteinuria, kidney lesion reduction and a decreased pathogenic aab response. At the end of the experiment at 29 weeks, 80% of all the treated rats had insignificantly low levels of circulating IgG aabs, indicating cessation of pathogenic aab production and corresponding termination of the disease process. In contrast, most untreated rats with the kidney disease still had high levels of circulating pathogenic aabs at the end of the experiment, which maintained disease progression.     

川芎嗪对大鼠被动型Heymann肾炎病变的影响

建立ＳＤ大鼠典型的被动型Ｈｅｙｍａｎｎ肾炎（ＰＨＮ）模型,观察川芎嗪对肾内血栓素Ａ２（ＴｘＡ２）．前列环素Ｉ２（ＰＧＩ２）及ＴＸＡ２－ＰＧＩ２平衡的影响。结果表明：川穹嗪能够降低大鼠尿中的ＴＸＡ２而提高ＰＧＩ２的含量。此外,对于减少尿蛋白的分泌及肾组织学的损伤也有一定的作用。提示川芎嗪可用于ＰＨＮ病变的防治。