Nrf2-deficient female mice develop lupus-like autoimmune nephritis

Keigyou Yoh, Ken Itoh, Akiko Enomoto, Aki Hirayama, Naoto Yamaguchi, Masaki Kobayashi, Naoki Morito, Akio Koyama, Masayuki Yamamoto, Satoru Takahashi

Research output: Contribution to journalArticlepeer-review

267 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1343-1353
Number of pages11
JournalKidney international
Volume60
Issue number4
DOIs
Publication statusPublished - 2001
Externally publishedYes

Keywords

  • Antioxidant enzymes
  • Autoimmune disease
  • Cell injury
  • Oxidative stress
  • Transcriptional activator

ASJC Scopus subject areas

  • Nephrology

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