TY - JOUR
T1 - Nrf2-deficient female mice develop lupus-like autoimmune nephritis
AU - Yoh, Keigyou
AU - Itoh, Ken
AU - Enomoto, Akiko
AU - Hirayama, Aki
AU - Yamaguchi, Naoto
AU - Kobayashi, Masaki
AU - Morito, Naoki
AU - Koyama, Akio
AU - Yamamoto, Masayuki
AU - Takahashi, Satoru
N1 - Funding Information:
This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture, the Japanese Society for Promotion of Sciences (RFTF), Core Research for Evolutional Sciences and Technology (CREST), and Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN). We thank S. Nagase, Y. Katoh, N. Wakabayashi, Y. Tokoro, R. Shimizu (University of Tsukuba), M. Nose (Ehime University), Vincent Kelly (Banyu Pharmaceutical Co., Ltd.), K-C Lim and P.W. Stevens (Northwestern University) for their help and discussion. We also thank N. Kaneko, N. Sugae, and E. Noguchi (University of Tsukuba) for their excellent assistance.
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
KW - Antioxidant enzymes
KW - Autoimmune disease
KW - Cell injury
KW - Oxidative stress
KW - Transcriptional activator
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U2 - 10.1046/j.1523-1755.2001.00939.x
DO - 10.1046/j.1523-1755.2001.00939.x
M3 - Article
C2 - 11576348
AN - SCOPUS:0034785941
VL - 60
SP - 1343
EP - 1353
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 4
ER -