Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice
Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice
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DOI：
10.1111/j.1365-2249.2010.04245.x
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发表时间：
2010-11-01
影响因子：
4.6
通讯作者：
Zhang, X. K.
中科院分区：
文献类型：
--
作者：
Mathenia, J.;Reyes-Cortes, E.;Zhang, X. K.
转录因子Fli-1与小鼠和人狼疮的发病机制有关。狼疮患者外周血淋巴细胞中Fli-1 mRNA水平升高；此外，在正常小鼠中转基因过表达Fli-1导致狼疮样疾病的发展。狼疮肾炎是狼疮患者和动物模型死亡的主要原因。在本研究中，我们产生了Fli-1杂合敲除（Fli-1+/-）的NZM2410小鼠（其中野生型是广泛使用的狼疮小鼠模型），其Fli-1表达水平降低，并研究了Fli-1表达对狼疮肾炎发展和生存的影响。93%的Fli-1+/- NZM2410小鼠存活到52周，而野生型NZM2410小鼠只有35%。在30和34周龄时，Fli-1+/- NZM2410小鼠的自身抗体，包括抗dsdna和抗肾小球基底抗原，与野生型NZM2410小鼠相比，有统计学意义显著降低。与野生型相比，Fli-1+/- NZM2410小鼠脾脏总B细胞和活化B细胞数量明显减少。与野生型NZM2410小鼠相比，Fli-1+/- NZM2410小鼠的蛋白尿和肾脏病理评分也显著减少。与野生型小鼠相比，Fli-1+/- NZM2410小鼠肾脏中早期生长反应1 （Egr-1）的表达显著降低。我们的数据表明，Fli-1的表达在NZM2410小鼠狼疮疾病的发展中起重要作用。
P>The transcription factor Fli-1 is implicated in the pathogenesis of both murine and human lupus. Increased levels of Fli-1 mRNA were present in the peripheral blood lymphocytes from lupus patients; furthermore, transgenic overexpression of Fli-1 in normal mice resulted in the development of a lupus-like disease. Lupus nephritis is a major cause of death in both lupus patients as well as in animal models. In this study, we generated Fli-1 heterozygous knockout (Fli-1+/-) NZM2410 mice (of which the wild-type is a widely used lupus murine model) that expressed decreased levels of Fli-1 and investigated the impact of Fli-1 expression on lupus nephritis development and survival. Ninety-three per cent of the Fli-1+/- NZM2410 mice survived to the age of 52 weeks compared to only 35% of wild-type NZM2410 mice. Autoantibodies, including anti-dsDNA and anti-glomerular basement antigen, in Fli-1+/- NZM2410 mice were statistically significantly lower when compared to wild-type NZM2410 mice at the ages of 30 and 34 weeks. Total B cell and activated B cell populations in the spleens from Fli-1+/- NZM2410 mice were decreased significantly compared to wild-type NZM2410 mice. Fli-1+/- NZM2410 mice also had remarkably diminished proteinuria and decreased renal pathological scores when compared with wild-type NZM2410 mice. Expression of early growth response 1 (Egr-1) was decreased significantly in the kidneys from Fli-1+/- NZM2410 mice when compared to wild-type littermates. Our data indicate that expression of Fli-1 plays an important role in lupus disease development in NZM2410 mice.