Complement receptor 1–related gene/protein y (Crry) is a potent murine membrane complement regulator that inhibits classical and alternative pathway C3 convertases. In nephrotoxic serum (NTS) nephritis, injected antibodies (Abs) bind to glomeruli, leading to complement activation and subsequent glomerular injury and albuminuria. To study the phenotypic effects of continuous complement pathway blockade, transgenic mice were created that express recombinant soluble (rs) Crry directed by the broadly active and heavy metal-inducible metallothionein-I promoter. One transgenic line expressing high levels of rsCrry was propagated. Serum rsCrry levels were 18.7 ± 2.7 μg/ml (n = 5) at basal level and increased to 118.1 ± 20.6 μg/ml 4 d after addition of zinc to the drinking water. By reverse transcription polymerase chain reaction (RT-PCR), transgene messenger (m)RNA was present in liver, kidney, brain, lung, and spleen, but not in heart. By in situ RT-PCR analysis of kidneys, transgene mRNA was widely expressed both in renal glomeruli and tubules. Urinary excretion of rsCrry was 113.4 ± 22.4 μg/ml with a fractional excretion relative to creatinine of 13.2 ± 2.7%, consistent with local renal production of rsCrry and secretion into urine. The founder and all transgene positive adult animals have remained healthy with no mortality or apparent phenotypic abnormalities, including infection or immune complex disease. To determine whether rsCrry blocked complement-mediated injury, NTS nephritis was induced by injection of NTS immunoglobulin (Ig)G, followed by an 18-h urine collection to quantitate the excretion of albumin as a measure of glomerular injury. In transgene-negative littermates (n = 15), transgene-positive animals (n = 10), and transgene-positive animals fed zinc (n = 10), albuminuria was 4,393 ± 948, 1,783 ± 454, and 1,057 ± 277 μg/mg creatinine, respectively (P < 0.01 by ANOVA). Glomerular C3 was evident by immunofluorescence staining in 12/15 transgene-negative animals, but in none of the transgene-positive animals fed zinc. Thus, we have produced the first transgenic animals that overexpress a soluble C3 convertase inhibitor. rsCrry expression markedly ameliorates an Ab-induced disease model in vivo. These results support the hypothesis that continuous complement inhibition at the C3 convertase step is feasible and effective in complement-mediated injury states.
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5 October 1998
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October 05 1998
Transgenic Mice Overexpressing the Complement Inhibitor Crry as a Soluble Protein Are Protected from Antibody-induced Glomerular Injury
Richard J. Quigg,
Richard J. Quigg
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Chun He,
Chun He
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Alice Lim,
Alice Lim
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Dawn Berthiaume,
Dawn Berthiaume
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Jessy J. Alexander,
Jessy J. Alexander
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Damian Kraus,
Damian Kraus
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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V. Michael Holers
V. Michael Holers
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
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Richard J. Quigg
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Chun He
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Alice Lim
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Dawn Berthiaume
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Jessy J. Alexander
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Damian Kraus
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
V. Michael Holers
From the *Department of Medicine, Section of Nephrology, The University of Chicago, Chicago, Illinois 60637; and the ‡Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, Colorado 80262
Address correspondence to Richard Quigg, Department of Medicine, Section of Nephrology, The University of Chicago, 5841 South Maryland Ave., MC 5100, Chicago, IL 60637. Phone: 773-702-0757; Fax: 773-702-4816; E-mail: [email protected]
Received:
April 14 1998
Revision Received:
July 02 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 188 (7): 1321–1331.
Article history
Received:
April 14 1998
Revision Received:
July 02 1998
Citation
Richard J. Quigg, Chun He, Alice Lim, Dawn Berthiaume, Jessy J. Alexander, Damian Kraus, V. Michael Holers; Transgenic Mice Overexpressing the Complement Inhibitor Crry as a Soluble Protein Are Protected from Antibody-induced Glomerular Injury . J Exp Med 5 October 1998; 188 (7): 1321–1331. doi: https://doi.org/10.1084/jem.188.7.1321
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