Increased Susceptibility of Decay-Accelerating Factor Deficient Mice to Anti-Glomerular Basement Membrane Glomerulonephritis

Sogabe, Hajime; Nangaku, Masaomi; Ishibashi, Yoshitaka; Wada, Takehiko; Fujita, Toshiro; Sun, Xiujun; Miwa, Takashi; Madaio, Michael P.; Song, Wen‐Chao

doi:10.4049/jimmunol.167.5.2791

Cited by 80 publications

(72 citation statements)

References 59 publications

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“…DAF is a GPI-bound complement regulatory protein that also inhibits the C3 convertase enzymes. Mice with a targeted deletion of the GPI-DAF (Daf1) gene, when injured by subnephritogenic doses of anti-glomerular basement membrane antibody in the ANTN model, developed glomerular disease that was absent in controls (36). Overall, these studies demonstrated that regulation of C3 activation is important in preventing renal damage but did not clarify whether tissue injury is mediated by the anaphylatoxins C3a and C5a or via lytic or sublytic MAC insertion.…”

Section: Discussionmentioning

confidence: 78%

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CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

Turnberg¹,

Botto²,

Warren³

et al. 2003

Journal of the American Society of Nephrology

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Abstract. CD59 is a complement regulatory protein that inhibits the terminal part of the complement system, the membrane attack complex (MAC), a mediator of renal injury. Mice deficient in the Cd59a gene (mCd59aϪ/Ϫ) were used to investigate the role of CD59 in experimentally induced accelerated nephrotoxic nephritis, a model of immune complex-mediated glomerulonephritis. After accelerated nephrotoxic nephritis was induced by administration of sheep nephrotoxic globulin, mCd59aϪ/Ϫ mice and strain-matched controls on two genetic backgrounds, 129/Sv ϫ C57BL/6 and 129/Sv, were examined. For both, mCd59aϪ/Ϫ mice developed significantly greater glomerular cellularity than wild-type (WT) mice at day 5 after administration. At day 10 post-administration, mCd59aϪ/Ϫ mice exhibited more glomerular thrombosis than WT mice (thrombosis score, 1.8 [range, 1.4 to 4.0] versus 0.8 [range, 0.2 to 1.5] quadrants thrombosed per glomerulus, respectively; P ϭ 0.0006). In the majority of experiments, mCd59aϪ/Ϫ mice also had significantly more proteinuria than controls; however, there was no difference in serum creatinine or albumin. Quantitative immunofluorescence of kidney sections revealed significantly more C9 (as a marker of MAC) deposition within glomeruli of mCd59aϪ/Ϫ mice than WT controls (P Ͻ 0.001). There was no difference in deposition of C3 and sheep IgG between the two experimental groups. The lack of CD59a, by allowing unregulated MAC deposition, exacerbates the renal injury in this model of immune complex-mediated glomerulonephritis.

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Section: Discussionmentioning

confidence: 78%

“…Among the several factors that have been implicated in the pathogenesis of this disease, the roles of Fc␥ receptors (34) and complement (35)(36)(37) have been most comprehensively investigated. Although the involvement of Fc␥ receptors in immune complex-mediated nephritis is well documented, the role of complement in this model is still controversial.…”

mentioning

confidence: 99%

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

Turnberg¹,

Botto²,

Warren³

et al. 2003

Journal of the American Society of Nephrology

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“…During the preparation of this article, a report appeared by Sogabe and associates (Sogabe et al, 2001) that examined the effect of DAF deficiency in a model Electron microscopic examination of glomeruli from wild-type mice given NTS (A) show generally intact epithelial podocytes, with only segmental flattening and fusion (right side of field). In contrast, the epithelial podocytes in the knock-out mice given NTS (B) show extensive flattening and fusion and focal lipid vacuole formation (original magnification, ϫ20,000).…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with the findings described in this study, they similarly observed greater susceptibility to glomerular damage in Daf1 knock-out mice relative to wild-type controls despite equal renal expression of Crry. The predominant effect of DAF-deficiency in the studies by Sogabe et al (2001) seemed to be an increase in glomerular cellularity. Albuminuria was absent in the wild-type control mice and was mildly but significantly increased in the knock-out mice.…”

Section: Lin Et Almentioning

confidence: 99%

Decay-Accelerating Factor Confers Protection Against Complement-Mediated Podocyte Injury in Acute Nephrotoxic Nephritis

Lin

Emancipator

Salant

et al. 2002

Laboratory Investigation

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SUMMARY:Decay-accelerating factor (DAF or CD55) is one of a set of regulators that function to protect self cells from deposition of autologous C3b on their surfaces. Its relative importance in vivo, however, is incompletely understood. As one approach to address this issue, we induced nephrotoxic serum (NTS) nephritis in wild-type mice and Daf1 gene-floxed mice devoid of renal DAF expression. For these experiments NTS IgG was administered at a dose (0.5 mg iv) that requires complement for glomerular injury. After 18 hours, renal injury was assessed by proteinuria and by histologic, immunohistochemical, and electron microscopic analyses of kidneys. Fifteen normal and 15 DAF-deficient mice were studied. Baseline albuminuria in the Daf1 Ϫ/Ϫ mice was 115.9 Ϯ 41.4 g/mg creatinine as compared with 85.7 Ϯ 32.3 g/mg creatinine in their Daf1 ϩ/ϩ littermates (p ϭ 0.075). After administration of NTS IgG, albuminuria increased to 2001.7 Ϯ 688.7 g/mg creatinine as compared with 799.7 Ϯ 340.5 g/mg creatinine in the controls (p ϭ 0.0003). Glomerular histology was similar in Daf1 Ϫ/Ϫ and Daf1 ϩ/ϩ mice, with essentially no infiltrating leukocytes. In contrast, electron microscopy revealed severe podocyte fusion in the Daf1 Ϫ/Ϫ mice but only mild focal changes in the controls. Immunohistochemical staining showed equivalent deposition of the administered (sheep) NTS IgG in the Daf1 Ϫ/Ϫ and Daf1 ϩ/ϩ animals. This contrasted with marked deposition of autologous murine C3 in the former and minimal deposition in the latter. The results show that DAF is essential physiologically for protecting glomeruli against autologous complement attack initiated by the classical pathway. (Lab Invest 2002, 82:563-569).D ifferent forms of nephrotoxic serum (NTS)-induced nephritis in rats and mice have been widely utilized as animal models for human antibodyinduced renal diseases (reviewed in Salant and Cybulsky, 1988). The mechanism of glomerular damage differs, depending on the source and dose of the antibody and the time after antibody administration (Boyce and Holdsworth, 1985;Salant and Cybulsky, 1988). When a low dosage of sheep NTS is given to mice, complement plays a significant role in the early heterologous phase of nephritis (Hebert et al, 1998;Quigg et al, 1998aQuigg et al, , 1998bSchrijver et al, 1988). This has been verified either by depleting serum complement proteins with cobra venom factor (Quigg et al, 1998b) or using C3 or C4 knock-out mice (Hebert et al, 1998). When the dosage of NTS is increased, the disease is in large part antibody mediated, and dependence on complement is diminished (Hebert et al, 1998). During the later autologous phase, especially if accelerated by preimmunization with heterologous IgG, a more fulminant, leukocyte-rich inflammatory lesion is induced (Lloyd et al, 1997).The sheep NTS used in these studies is specific for several podocyte cell surface proteins, including some that are known to be nephritogenic (Chugh et al, 2001). In addition, the proteinuria that develops in the early heterologous phase of g...

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“…13,14 These mice were originally on a mixed C57BL/6 and 129 background, and were backcrossed onto the Balb/c strain for at least 10 generations. Homozygous DAF KO and CD59 KO mice were generated by intercrossing heterozygous mice and screened by flow cytometry as described.…”

Section: Materials and Methods Protocols For Animal Workmentioning

confidence: 99%

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

Bao

Haas

Minto

et al. 2007

Laboratory Investigation

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The complex balance between the pro-activating and regulatory influences of the complement system can affect the pathogenesis of immune complex-mediated glomerulonephritis (ICGN). Key complement regulatory proteins include decay accelerating factor (DAF) and CD59, which inhibit C3 activation and C5b-9 generation, respectively. Both are glycosylphosphatidylinositol-linked cell membrane proteins, which are widely distributed in humans and mice. Chronic serum sickness induced by daily immunization with horse spleen apoferritin over 6 weeks was used to induce ICGN in DAF-, CD59-and DAF/CD59-deficient mice, with wild-type littermate mice serving as controls. Both DAF and DAF/CD59-deficient mice had an increased incidence of GN relative to wild-type controls associated with significantly increased glomerular C3 deposition. Disease expression in CD59-deficient mice was no different than wild-type controls. DAF-and DAF/CD59-deficient mice also had increased monocyte chemoattractant protein-1 mRNA expression and glomerular infiltration with CD45 þ leukocytes. Our findings suggest that activation of C3 is strongly associated with experimental ICGN while downstream formation of C5b-9 is of lesser pathogenic importance in this model.

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Increased Susceptibility of Decay-Accelerating Factor Deficient Mice to Anti-Glomerular Basement Membrane Glomerulonephritis

Cited by 80 publications

References 59 publications

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice

Decay-Accelerating Factor Confers Protection Against Complement-Mediated Podocyte Injury in Acute Nephrotoxic Nephritis

Decay-accelerating factor but not CD59 limits experimental immune-complex glomerulonephritis

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