Effects of complement factor D deficiency on the renal disease of MRL/lpr mice

Margaret K. Elliott, Tambi Jarmi, Phillip Ruiz, Yuanyuan Xu, V. Michael Holers, Gary S. Gilkeson

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)129-138
Number of pages10
JournalKidney International
Volume65
Issue number1
DOIs
StatePublished - Jan 1 2004
Externally publishedYes

Fingerprint

Inbred MRL lpr Mouse
Alternative Complement Pathway
Kidney
Creatinine
Immunoglobulin G
Major Histocompatibility Complex
Proteinuria
Autoantibodies
Haplotypes
Complement Factor D Deficiency
Lupus Nephritis
Periodic Acid
Zymosan
Glutaral
Hematoxylin
Eosine Yellowish-(YS)
Fluorescein
Serum
Systemic Lupus Erythematosus
Genes

Keywords

  • Animal models
  • Complement alternative pathway
  • Lupus nephritis

ASJC Scopus subject areas

  • Nephrology

Cite this

Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. / Elliott, Margaret K.; Jarmi, Tambi; Ruiz, Phillip; Xu, Yuanyuan; Holers, V. Michael; Gilkeson, Gary S.

In: Kidney International, Vol. 65, No. 1, 01.01.2004, p. 129-138.

Research output: Contribution to journalArticle

Elliott, Margaret K. ; Jarmi, Tambi ; Ruiz, Phillip ; Xu, Yuanyuan ; Holers, V. Michael ; Gilkeson, Gary S. / Effects of complement factor D deficiency on the renal disease of MRL/lpr mice. In: Kidney International. 2004 ; Vol. 65, No. 1. pp. 129-138.
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AU - Gilkeson, Gary S.

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N2 - 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.

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