Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress
Peroxiredoxin 4 knockout results in elevated spermatogenic cell death via oxidative stress
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DOI：
10.1042/bj20081526
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发表时间：
2009-04-01
影响因子：
4.1
通讯作者：
Fujii, Junichi
中科院分区：
文献类型：
--
作者：
Iuchi, Yoshihito;Okada, Futoshi;Fujii, Junichi
过氧化物酶（peroxiredoxin，Prx）是一种多功能的氧化还原蛋白，具有硫氧还蛋白依赖的过氧化物酶活性。Prx 4在大多数组织中作为分泌蛋白存在，而在性成熟的睾丸中，它通过未切割的N-末端疏水肽锚定在生精细胞的ER（内质网）膜中。我们建立了Prx 4基因敲除小鼠来研究Prx 4在体内的功能。通过使Prx（thox/+）雌性小鼠与普遍表达Cre重组酶的Cre转基因雄性小鼠交配，获得在所有细胞中缺乏Prx 4表达的Prx 4小鼠。由此产生的Prx 4雄性小鼠具有生育能力，除了睾丸萎缩外，大多数器官的大小几乎正常。在Prx小鼠中，脱氧核苷酸转移酶介导的dUTP缺口末端标记阳性生精细胞的数量高于Prx 4小鼠，并且在43 ℃下加热下腹部15 min时显著增加。在Prx 4小鼠中，对4-羟基壬烯醛和8-羟基鸟嘌呤抗体反应的细胞较高，并伴随脂质和蛋白质硫醇氧化的升高。Prx 4小鼠的附睾尾部含有圆形精母细胞，这在Prx 4小鼠中没有发现，并显示少精子症。然而，来自Prx小鼠附睾的成熟精子在体外表现出正常的受精。总之，这些结果表明，缺乏Prx 4的生精细胞比其野生型对应物更容易通过氧化损伤而死亡。我们的研究结果表明，Prx 4的存在，最有可能的膜结合形式，是重要的精子发生，但不是所有的绝对必要的。
Prx (peroxiredoxin) is a multifunctional redox protein with thioredoxin-dependent peroxidase activity. Prx4 is present as a secretory protein ill Most tissues, whereas in sexually mature testes it is anchored in the ER (endoplasmic reticulum) membrane of spermatogenic cells via an uncleaved N-terminal hydrophobic peptide. We generated a Prx4 knockout mouse to investigate the function of Prx4 in vivo. Prx4 mice lacking Prx4 expression in all cells were obtained by mating Prx(thox/+) female mice with Cre-transgenic male mice that ubiquitously expressed Cre recombinase. The resulting Prx4 male mice were fertile, and most organs were nearly normal in size, except for testicular atrophy. The number deoxynucleotidyl transferase-mediated dUTP nick end labelling-positive spermatogenic cells was higher, in Prx mice than in Prx4 mice and increased remarkably in response it) warming the lower abdomen at 43 degrees C for 15 min. Cells reactive to antibodies against 4-hydroxynonenal and 8-hydroxyguanine were high in the Prx4 ' mice and concomitant with elevated oxidation of lipid and protein thiols. The cauda epididymis of Prx4 mice contained round spermatocytes, which were not found in Prx4 mice, and displayed oligozoospermia. However, mature spermatozoa from the epididymis of Prx mice exhibited normal fertilization in vitro. Taken together, these results indicate that spermatogenic cells lacking Prx4 are more Susceptible to cell death Via oxidative damage than their wild-type counterparts. Our results Suggest that the presence of Prx4, most likely the membrane-bound form, is important for spermatogenesis, but not all absolute requisite.