Transgenic Expression of a Soluble Complement Inhibitor Protects Against Renal Disease and Promotes Survival in MRL/lpr Mice
| Autor: | V. Michael Holers, Mark Haas, K. K. Culhane, Damian M. Kraus, Jessy J. Alexander, Richard J. Quigg, Susan A. Boackle, Randall K. Anderson, Pierce Park, Patrick N. Cunningham, Lihua Bao |
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| Rok vydání: | 2002 |
| Předmět: |
Genetically modified mouse
Mice Inbred MRL lpr medicine.medical_specialty Transgene Kidney Glomerulus Immunology Lupus nephritis Mice Transgenic Spleen urologic and male genital diseases Autoimmune Diseases Mice chemistry.chemical_compound Complement inhibitor Internal medicine medicine Animals Immunology and Allergy Transgenes skin and connective tissue diseases Blood urea nitrogen Complement Inactivator Proteins Creatinine Kidney business.industry Complement C3 medicine.disease Lupus Nephritis Survival Analysis Receptors Complement Mice Inbred C57BL medicine.anatomical_structure Endocrinology chemistry Immunoglobulin G Receptors Complement 3b business |
| Zdroj: | The Journal of Immunology. 168:3601-3607 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.168.7.3601 |
| Popis: | To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 ± 9 and 122 ± 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 ± 4.3 and 36.9 ± 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease. |
| Databáze: | OpenAIRE |
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