title: Nrf2-deficient female mice develop lupus-like autoimmune nephritis.
abstract: 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.
authors.affiliation: Institute of Basic Medical Sciences, Institute of Clinical Medicine and Center for TARA, University of Tsukuba, Tsukuba City, Ibaraki, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoh
authors.forename: K
authors.initials: K
authors.lastname: Itoh
authors.forename: A
authors.initials: A
authors.lastname: Enomoto
authors.forename: A
authors.initials: A
authors.lastname: Hirayama
authors.forename: N
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: N
authors.initials: N
authors.lastname: Morito
authors.forename: A
authors.initials: A
authors.lastname: Koyama
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001323:Autoantibodies / Q000032:analysis; D001327:Autoimmune Diseases / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001835:Body Weight; D003404:Creatinine / Q000097:blood / Q000652:urine; D004247:DNA / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D007668:Kidney / Q000473:pathology; D008054:Lipid Peroxides / Q000378:metabolism; D008181:Lupus Nephritis / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D051267:NF-E2-Related Factor 2; D009929:Organ Size; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000473:pathology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D004268:DNA-Binding Proteins; D008054:Lipid Peroxides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D004247:DNA; D003404:Creatinine