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- Title
CELL BIOLOGY - IMMUNOLOGY - PATHOLOGY Effects of complement factor D deficiency on the renal disease of MRL/ lpr mice.
- Authors
Elliott, Margaret K.; Jarmi, Tambi; Ruiz, Phil; Yuanyuan Xu; Holers, V. Michael; Gilkeson, Gary S.
- Abstract
Effects of complement factor D deficiency on the renal disease of MRL/ lpr mice. Background. The alternative complement pathway (AP) is activated in individuals with lupus nephritis and in murine models of systemic lupus erythematosus, including MRL/ lpr mice. A previous study from our laboratory evaluated the development of renal disease in MRL/ lpr mice genetically deficient in factor B (Bf−/−), a protein necessary for AP activation. MRL/ lpr Bf−/− mice developed less renal disease and had improved survival; however, these mice were also a different major histocompatibility complex (MHC) haplotype (H-2b) than their wild-type littermates (H-2k) due to the gene for Bf being located in the MHC gene complex. We undertook the current study to determine if the decreased renal disease in MRL/ lpr Bf−/− mice was due to the lack of AP activation or the H-2b haplotype by studying the effects of factor D (Df) deficiency, a critical protein for AP activation, on disease development in MRL/ lpr mice. Methods. Df-deficient mice were backcrossed with MRL/ lpr mice for four to nine generations. MRL/ lpr H-2k Df−/−, Df+/−, and Df+/+ littermates were evaluated for disease development. Lack of AP activation in MRL/ lpr Df−/− mice was determined by the zymosan assay. Serum creatinine levels were measured using a creatinine kit. Proteinuria and autoantibody levels were determined by enzyme-linked immunosorbent assay (ELISA). Sections from one kidney were stained with fluorescein isothiocyanate (FITC) α-murine C3 or α-murine IgG to detect C3 and IgG deposition. The remaining kidney was cut in half with one half fixed, sectioned, and stained with hematoxylin and eosin and periodic acid-Schiff (PAS) to evaluate pathology and another half fixed in glutaraldehyde and examined via electron microscopy. Results. MRL/ lpr Df−/− mice had similar glomerular IgG deposition, proteinuria and autoantibody levels, as Df+/+ and Df+/− littermates. However, glomerular C3 deposition, serum creatinine levels, and pathologic renal disease were significantly reduced in Df−/− mice. Despite the lack of renal disease in Df−/− mice, life span was not impacted by factor D deficiency. Conclusion. The absence of Df and AP activation is protective against the development of proliferative renal disease in MRL/ lpr mice suggesting the similar effect of Bf deficiency in MRL/ lpr mice was also due to the lack of AP activation.
- Subjects
KIDNEY diseases; PROTEINS; LABORATORY mice
- Publication
Kidney International, 2004, Vol 65, Issue 1, p129
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1111/j.1523-1755.2004.00371.x