Nrf2-deficient female mice develop lupus-like autoimmune nephritis

Kidney Int. 2001 Oct;60(4):1343-53. doi: 10.1046/j.1523-1755.2001.00939.x.


Background: NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcriptional activator essential for the coordinate transcriptional induction of antioxidant enzymes and phase II drug metabolizing enzymes through the antioxidant response element/electrophile response element. The Nrf2-deficient mice were found to develop normally under standard laboratory conditions. However, upon closer examination, we found that aged female Nrf2-deficient mice displayed a shortened lifespan and developed severe glomerulonephritis. The present study investigated the glomerulonephritis findings in Nrf2-deficient mice.

Methods: To evaluate glomerular lesions of Nrf2-deficient mice, histological and functional analyses were performed. The amounts of serum immunoglobulins, anti-double-stranded (ds) DNA antibody, and lipid peroxidation using thiobarbituric acid reactive substances (TBARS) also were measured.

Results: Nrf2-deficient female mice over 60 weeks of age developed severe nephritis characterized by cellular proliferation, lobular formation, crescent formation, and subepithelial electron-dense deposits. In immunofluorescent assays, Nrf2-deficient female mice showed mesangial deposits and massive granular deposits of IgG, IgM, and C3 along the capillary walls. Higher serum levels of IgG, anti-dsDNA antibody, lower creatinine clearance, and slight splenomegaly also were found in Nrf2-deficient female mice. A higher concentration of TBARS also was found in Nrf2-deficient female mice.

Conclusions: These data indicate that the aged Nrf2-deficient female mice develop lupus-like autoimmune nephritis and suggest that nrf2 is one of the genes determining susceptibility to autoimmune disease. Analysis of nephritis in the Nrf2-deficient female mouse may clarify the mechanisms leading to the development of lupus disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / analysis
  • Autoantibodies / analysis
  • Autoimmune Diseases / etiology*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • Body Weight
  • Creatinine / blood
  • Creatinine / urine
  • DNA / immunology
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • Female
  • Kidney / pathology
  • Lipid Peroxides / metabolism
  • Lupus Nephritis / etiology*
  • Lupus Nephritis / immunology
  • Lupus Nephritis / metabolism
  • Lupus Nephritis / pathology
  • Male
  • Mice
  • Mice, Knockout / genetics
  • NF-E2-Related Factor 2
  • Organ Size
  • Spleen / pathology
  • Survival Analysis
  • T-Lymphocyte Subsets / pathology
  • Trans-Activators / deficiency*
  • Trans-Activators / genetics


  • Antibodies, Antinuclear
  • Autoantibodies
  • DNA-Binding Proteins
  • Lipid Peroxides
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Trans-Activators
  • DNA
  • Creatinine