Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr

Naoki Morito, Keigyou Yoh, Aki Hirayama, Ken Itoh, Masato Nose, Akio Koyama, Masayuki Yamamoto, Satoru Takahashi

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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-α (TNF-α)-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-α-mediated apoptosis. Conclusion. These results indicate that a deficiency in Nrf2 enhances TNF-α-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.

Original languageEnglish
Pages (from-to)1703-1713
Number of pages11
JournalKidney international
Volume65
Issue number5
DOIs
Publication statusPublished - 2004 May
Externally publishedYes

Keywords

  • Apoptosis
  • Fas
  • Glutathione
  • Nrf2
  • Oxidative stress
  • TNF-α

ASJC Scopus subject areas

  • Nephrology

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