Morito Naoki, Yoh Keigyou, Hirayama Aki, Itoh Ken, Nose Masato, Koyama Akio, Yamamoto Masayuki, Takahashi Satoru
Institute of Basic Medical Sciences, Institute of Clinical Medicine and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Kidney Int. 2004 May;65(5):1703-13. doi: 10.1111/j.1523-1755.2004.00565.x.
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.
To investigate the mechanism whereby Nrf2 contributes to the susceptibility to autoimmune diseases, we generated nrf2-/-lpr/lpr mice.
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.
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.
Nrf2是一种碱性亮氨酸拉链转录激活因子，对抗氧化酶和II期药物代谢酶的协同转录诱导至关重要。我们之前报道过，Nrf2基因缺陷的雌性小鼠会发展为狼疮样自身免疫性肾炎（《肾脏病国际》60:1343 - 1353，2001年）。该结果表明，Nrf2可能是决定自身免疫性疾病易感性的候选基因。MRL/lpr小鼠存在Fas介导的凋亡缺陷，由于自身抗体的产生而发展为肾小球肾炎。
为了研究Nrf2导致自身免疫性疾病易感性的机制，我们培育了nrf2 - / - lpr/lpr小鼠。
出乎意料的是，nrf2 - / - lpr/lpr雌性小鼠的寿命显著延长，与nrf2 + / + lpr/lpr雌性小鼠相比，这些小鼠的肾炎症状有所改善。nrf2 - / - lpr/lpr雌性小鼠的免疫异常和高球蛋白血症也得到缓解。此外，由于细胞凋亡增加，淋巴结病受到抑制。为了阐明导致细胞凋亡刺激的分子机制，我们分析了nrf2 - / - lpr/lpr小鼠对死亡信号的反应。我们发现nrf2 - / - lpr/lpr小鼠对肿瘤坏死因子-α（TNF-α）介导的细胞凋亡敏感。由于Nrf2缺陷细胞内的谷胱甘肽水平降低，谷胱甘肽水平的长期耗竭可能导致TNF-α介导的细胞凋亡增强。
这些结果表明Nrf2缺陷增强了TNF-α介导的细胞凋亡，进而改善了由lpr基因突变引起的异常凋亡反应。因此，Nrf2缺陷起到了自身免疫加速基因lpr的抑制作用。
