title: Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr.
abstract: BACKGROUND
  Nrf2 is a basic leucine zipper transcriptional activator essential for the coordinate transcriptional induction of antioxidant and phase II drug metabolizing enzymes. We previously reported that Nrf2-deficient female mice develop lupus-like autoimmune nephritis (Kidney Int 60:1343-1353, 2001). The result suggested that nrf2 is a possible candidate gene in determining susceptibility to autoimmune diseases. MRL/lpr mice, defective in Fas-mediated apoptosis, develop glomerulonephritis due to the production of autoantibodies.
  
  
  METHODS
  To investigate the mechanism whereby Nrf2 contributes to the susceptibility to autoimmune diseases, we generated nrf2-/-lpr/lpr mice.
  
  
  RESULTS
  Unexpectedly, the lifespan of nrf2-/-lpr/lpr female mice was markedly prolonged and these mice showed an improvement in nephritis compared to nrf2+/+lpr/lpr female mice. Immunologic abnormalities and hypergammaglobulinemia were also alleviated in nrf2-/-lpr/lpr female mice. Furthermore, lymphadenopathy was suppressed as a result of increased apoptosis. To elucidate the molecular mechanism causing a stimulation of apoptosis, we analyzed the response made by nrf2-/-lpr/lpr mice to death signals. We show that nrf2-/-lpr/lpr mice are sensitive to tumor necrosis factor-alpha (TNF-alpha)-mediated apoptosis. Since intracellular glutathione levels are decreased in Nrf2-deficient cells, it is probable that a prolonged depletion in glutathione levels leads to the enhancement in TNF-alpha-mediated apoptosis.
  
  
  CONCLUSIONS
  These results indicate that a deficiency in Nrf2 enhances TNF-alpha-mediated apoptosis which in-turn ameliorates the abnormal apoptotic response that arises from a mutation in the lpr gene. Therefore, Nrf2 deficiency acts as a suppressor of the autoimmune accelerating gene lpr.
authors.affiliation: Institute of Basic Medical Sciences, Institute of Clinical Medicine and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Morito
authors.forename: Keigyou
authors.initials: K
authors.lastname: Yoh
authors.forename: Aki
authors.initials: A
authors.lastname: Hirayama
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Masato
authors.initials: M
authors.lastname: Nose
authors.forename: Akio
authors.initials: A
authors.lastname: Koyama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D001483:Base Sequence; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D016350:Leucine Zippers; D008181:Lupus Nephritis / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009154:Mutation; D051267:NF-E2-Related Factor 2; D009393:Nephritis / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor
chemical_list: D000974:Antibodies, Antinuclear; D016207:Cytokines; D004268:DNA-Binding Proteins; C491899:Fas protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D018124:Receptors, Tumor Necrosis Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004247:DNA; D005978:Glutathione