C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy

Williams, Allison L; Gullipalli, Damodar; Ueda, Yoshiyasu; Sato, Sayaka; Zhou, Lin; Miwa, Takashi; Tung, Kenneth S. K.; Song, Wen‐Chao

doi:10.1016/j.kint.2016.11.018

Cited by 26 publications

(29 citation statements)

References 42 publications

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“…The exact nature of activated C3 fragments deposited in the FH m/m P 2/2 mouse glomeruli remains to be established, but glomerular staining could also be detected using two commercial antibodies against C3b/iC3b/C3d or C3d (Supplemental Figure 2). Because C3, FB, and to a lesser extent, C5 were excessively consumed in FH m/m P 2/2 mice, 5,10 we next examined if treatment with CRIg-Fc led to recovery of these complement components in the plasma. Figure 4 shows that control IgG treatment had no effect on plasma C3, FB, and C5 levels, but CRIg-Fc treatment resulted in significant elevation of plasma C3, C5, and FB proteins.…”

Section: Resultsmentioning

confidence: 99%

“…blood urea nitrogen (BUN), serum creatinine, proteinuria, leukocyturia, and hematuria were assessed as described. 5,10,31 Immunofluorescence Staining and Histology Immunofluorescence staining of C3, C9, and fibrin in the mouse kidney, preparation of paraffin sections and hematoxylin and eosin and periodic acid-Schiff staining of kidney sections were performed as described previously. 5,10,32 In some experiments, glomerular C3 deposition was also stained with a FITC-conjugated mouse anti-mouse C3b/iC3b/C3d mAb (used at 1 mg/ml; Cederlane Labs) or a biotinylated polyclonal goat anti-mouse C3d antibody (catalog #BAF2655, used at 1 mg/ml; R&D Systems) with streptavidin-FITC (catalog #554060, used at 1:100 dilution; BD Pharmingen) as a detecting reagent.…”

Section: Measurement Of Renal Functionmentioning

confidence: 99%

“…5 Western Blotting of C3, FB, and C5 Western blotting of mouse plasma C3, FB, and C5 was performed as described. 5,10 Detection of Anti CRIg-Fc Antibody Response To detect antibody response against CRIg-Fc, ELISA plates were coated with 2 mg/ml purified CRIg-Fc in PBS for 1 hour at 37°C…”

Section: Measurement Of Renal Functionmentioning

confidence: 99%

“…These data provides initial proof of concept for the therapeutic efficacy of CRIg-Fc, with potential implications for the development of a therapeutic agent to treat patients with C3G. pathogenesis, [10][11][12][13][14][15][16][17] and the blood level of soluble C5b-9 (sC5b-9) has been used as a biomarker for disease activity and predicted response of anti-C5 therapy. 11,14,16,18,19 Prognosis of C3G, particularly DDD, is poor and approximately 50% patients progress to end stage renal failure within 10 years of diagnosis.…”

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confidence: 96%

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Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily

Wang

Campagne²,

Katschke³

et al. 2018

JASN

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C3 glomerulopathy (C3G) is a life-threatening kidney disease caused by dysregulation of the alternative pathway of complement (AP) activation. No approved specific therapy is available for C3G, although an anti-C5 mAb has been used off-label in some patients with C3G, with mixed results. Thus, there is an unmet medical need to develop other inhibitors of complement for C3G. We used a murine model of lethal C3G to test the potential efficacy of an Fc fusion protein of complement receptor of the Ig superfamily (CRIg-Fc) in the treatment of C3G. CRIg-Fc binds C3b and inhibits C3 and C5 convertases of the AP. Mice with mutations in the factor H and properdin genes (FHP) develop early-onset C3G, with AP consumption, high proteinuria, and lethal crescentic GN. Treatment of FHP mice with CRIg-Fc, but not a control IgG, inhibited AP activation and diminished the consumption of plasma C3, factor B, and C5. CRIg-Fc-treated FHP mice also had significantly improved survival and reduced proteinuria, hematuria, BUN, glomerular C3 fragment, C9 and fibrin deposition, and GN pathology scores. Therapeutics developed on the basis of the mechanism of action of soluble CRIg may be effective for the treatment of C3G and should be explored clinically.

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Section: Resultsmentioning

confidence: 99%

Section: Measurement Of Renal Functionmentioning

confidence: 99%

Section: Measurement Of Renal Functionmentioning

confidence: 99%

mentioning

confidence: 96%

See 2 more Smart Citations

Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily

Wang

Campagne²,

Katschke³

et al. 2018

JASN

Self Cite

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“…For therapeutic studies, 4-week-old FH R/R mice of mixed sexes were treated for 8 weeks with the anti-P mAb 14E1 11 or an isotype murine IgG1 control mAb (MOPC 31C) 24 at 1 mg per mouse administered intraperitoneally. Control mAb was administered weekly, and anti-P mAb was given either once weekly or twice weekly as specified in Results and figures.…”

Section: Treatment Of Fh R/r With Anti-p or Isotype Control Mabmentioning

confidence: 99%

Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia

Ueda

Miwa

Gullipalli

et al. 2018

JASN

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Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of complement-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain. We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FH), that causes aHUS and systemic thrombophilia with high mortality. P deficiency completely rescued FH mice from premature death and prevented thrombocytopenia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FH mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FH mice after 4 weeks of anti-P mAb treatment. One half of the FH mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FH mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice. These results contrast with the detrimental effect of P inhibition observed in a murine model of C3 glomerulopathy and suggest that P contributes critically to aHUS pathogenesis. Inhibition of P in aHUS may be of therapeutic benefit.

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The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

et al. 2018

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Properdin is known as the only positive regulator of the complement system. Properdin promotes the activity of this defense system by stabilizing its key enzymatic complexes: the complement alternative pathway (AP) convertases. Besides, some studies have indicated a role for properdin as an initiator of complement activity. Though the AP is a powerful activation route of the complement system, it is also involved in a wide variety of autoimmune and inflammatory diseases, many of which affect the kidneys. The role of properdin in regulating complement in health and disease has not received as much appraisal as the many negative AP regulators, such as factor H. Historically, properdin deficiency has been strongly associated with an increased risk for meningococcal disease. Yet only recently had studies begun to link properdin to other complement-related diseases, including renal diseases. In the light of the upcoming complement-inhibiting therapies, it is interesting whether properdin can be a therapeutic target to attenuate AP-mediated injury. A full understanding of the basic concepts of properdin biology is therefore needed. Here, we first provide an overview of the function of properdin in health and disease. Then, we explore its potential as a therapeutic target for the AP-associated renal diseases C3 glomerulopathy, atypical hemolytic uremic syndrome, and proteinuria-induced tubulointerstitial injury. Considering current knowledge, properdin-inhibiting therapy seems promising in certain cases. However, knowing the complexity of properdin's role in renal pathologies in vivo, further research is required to clarify the exact potential of properdin-targeted therapy in complement-mediated renal diseases.

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C5 inhibition prevents renal failure in a mouse model of lethal C3 glomerulopathy

Cited by 26 publications

References 42 publications

Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily

Prevention of Fatal C3 Glomerulopathy by Recombinant Complement Receptor of the Ig Superfamily

Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia

The role of properdin in complement-mediated renal diseases: a new player in complement-inhibiting therapy?

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