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Morito, N. et al.

Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr.

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. CONCLUSION: 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.[1]

References

Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr. Morito, N., Yoh, K., Hirayama, A., Itoh, K., Nose, M., Koyama, A., Yamamoto, M., Takahashi, S. Kidney Int. (2004) [Pubmed]

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