Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line
Enhanced cadmium-induced testicular necrosis and renal proximal tubule damage caused by gene-dose increase in a Slc39a8-transgenic mouse line
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DOI：
10.1152/ajpcell.00409.2006
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发表时间：
2007-04-01
影响因子：
5.5
通讯作者：
Nebert, Daniel W.
中科院分区：
文献类型：
--
作者：
Wang, Bin;Schneider, Scott N.;Nebert, Daniel W.
对镉（Cd）诱导的睾丸坏死的抗性是一种常染色体隐性性状，定义为Cdm基因座。使用定位克隆，我们先前鉴定了Slc 39 a8（编码顶端表面ZIP 8转运蛋白）作为最可能负责表型的基因。原位杂交显示，睾丸血管内皮细胞表达高水平的ZIP 8在两个敏感的近交系小鼠品系和两个耐药品系可忽略不计的量。在本研究中，我们从镉敏感的129/ SvJ细菌人工染色体（BAC）文库中分离了一个168.7- kb的细菌人工染色体（BAC），仅携带Slc 39 a8基因，并产生BAC转基因小鼠。BTZIP 8 -3系具有三个拷贝的129/SvJSlc 39 a8基因插入Cd抗性C57 BL/6 J基因组（具有其正常的两个拷贝的Slc 39 a8基因），显示出与野生型小鼠相似的组织特异性ZIP 8 mRNA表达，主要在肺、睾丸和肾中.类似于2.5倍的高表达证实了BTZIP 8 -3系具有Slc 39 a8基因的五个拷贝而野生型小鼠具有Slc 39 a8基因的两个拷贝的事实。BTZIP 8 -3小鼠睾丸血管内皮细胞中ZIP 8 mRNA和蛋白表达明显增强。镉治疗逆转镉抗性（在非转基因同窝出生），镉敏感性BTZIP 8 -3小鼠的睾丸坏死表型的逆转证实，Slc 39 a8是明确的Cdm基因座。ZIP 8还特异性地定位于BTZIP 8 -3肾中的近端小管细胞的顶面。镉治疗引起急性肾功能衰竭和近端肾小管损伤的迹象BTZIP 8 - 3，但不是非转基因的同窝出生。BTZIP 8 - 3小鼠是研究镉致肾脏损害的理想动物模型。
Resistance to cadmium ( Cd)- induced testicular necrosis is an autosomal recessive trait defined as the Cdm locus. Using positional cloning, we previously identified the Slc39a8 ( encoding an apical- surface ZIP8 transporter protein) as the gene most likely responsible for the phenotype. In situ hybridization revealed that endothelial cells of the testis vasculature express high ZIP8 levels in two sensitive inbred mouse strains and negligible amounts in two resistant strains. In the present study, we isolated a 168.7- kb bacterial artificial chromosome ( BAC), carrying only the Slc39a8 gene, from a Cd- sensitive 129/ SvJ BAC library and generated BAC-transgenic mice. The BTZIP8-3 line, having three copies of the 129/ SvJ Slc39a8 gene inserted into the Cd- resistant C57BL/6J genome ( having its normal two copies of the Slc39a8 gene), showed tissue- specific ZIP8 mRNA expression similar to wild- type mice, mainly in lung, testis, and kidney. The similar to 2.5- fold greater expression paralleled the fact that the BTZIP8-3 line has five copies, whereas wild- type mice have two copies, of the Slc39a8 gene. The ZIP8 mRNA and protein localized especially to endothelial cells of the testis vasculature in BTZIP8-3 mice. Cd treatment reversed Cd resistance ( seen in nontransgenic littermates) to Cd sensitivity in BTZIP8-3 mice; reversal of the testicular necrosis phenotype confirms that Slc39a8 is unequivocally the Cdm locus. ZIP8 also localized specifically to the apical surface of proximal tubule cells in the BTZIP8-3 kidney. Cd treatment caused acute renal failure and signs of proximal tubular damage in the BTZIP8- 3 but not nontransgenic littermates. BTZIP8- 3 mice should be a useful model for studying Cd- induced disease in kidney.