Effects of Complement Factor D Deficiency on the Renal Disease of MRL/lpr Mice

Kidney Int. 2004 Jan;65(1):129-38. doi: 10.1111/j.1523-1755.2004.00371.x.

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) alpha-murine C3 or alpha-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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Autoantibodies / blood
  • Complement C3 / metabolism
  • Complement Factor D / deficiency
  • Complement Factor D / genetics*
  • Complement Pathway, Alternative / physiology*
  • Creatinine / blood
  • Female
  • Glomerulonephritis, Membranoproliferative / immunology
  • Glomerulonephritis, Membranoproliferative / mortality
  • Glomerulonephritis, Membranoproliferative / pathology
  • Glomerulonephritis, Membranoproliferative / physiopathology
  • Immunoglobulin G / metabolism
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / ultrastructure
  • Lupus Nephritis / immunology
  • Lupus Nephritis / mortality
  • Lupus Nephritis / pathology*
  • Lupus Nephritis / physiopathology*
  • Male
  • Mice
  • Mice, Inbred MRL lpr
  • Microscopy, Electron
  • Proteinuria / immunology
  • Proteinuria / mortality
  • Proteinuria / pathology
  • Proteinuria / physiopathology
  • Survival Rate

Substances

  • Autoantibodies
  • Complement C3
  • Immunoglobulin G
  • Creatinine
  • Complement Factor D
  • complement factor D, mouse