Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice
Reduced arsenic clearance and increased toxicity in aquaglyceroporin-9-null mice
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DOI：
10.1073/pnas.0908108106
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发表时间：
2009-09-15
影响因子：
11.1
通讯作者：
Mukhopadhyay, Rita
中科院分区：
文献类型：
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作者：
Carbrey, Jennifer M.;Song, Linhua;Mukhopadhyay, Rita
在肝脏中表达，水甘油孔蛋白-9（AQP 9）被甘油、亚砷酸盐和其他小的中性溶质渗透。为了评估可能的保护作用，评估了AQP 9缺失小鼠的体内砷毒性。注射NaAsO 2后，AQP 9缺失小鼠的存活率（LD 50，12 mg/kg）低于WT小鼠（LD 50，15 mg/kg）。砷的最高组织水平是在心脏中，AQP 9缺失小鼠积累的砷是WT小鼠的10-20倍。注射NaAsO 2后数小时内，AQP 9缺失小鼠持续严重心动过缓，尽管血清电解质正常。增加的砷水平也存在于AQP 9基因敲除小鼠的肝、肺、脾和睾丸中。AQP 9缺失小鼠粪便和尿液中的砷水平仅约为WT水平的10%，AQP 9缺失小鼠对多种砷物质的清除率降低表明AQP 9参与多种形式砷的输出。免疫组织化学染色显示，AQP 9是最丰富的肝细胞的基底外侧膜邻近窦状隙。PCR和免疫组化均未检测到心脏和肾脏中的AQP 9。我们认为AQP 9提供了肝脏排泄砷的途径，从而部分保护整个动物免受砷中毒的影响。
Expressed in liver, aquaglyceroporin-9 (AQP9) is permeated by glycerol, arsenite, and other small, neutral solutes. To evaluate a possible protective role, AQP9-null mice were evaluated for in vivo arsenic toxicity. After injection with NaAsO2, AQP9-null mice suffer reduced survival rates (LD50, 12 mg/kg) compared with WT mice (LD50, 15 mg/kg). The highest tissue level of arsenic is in heart, with AQP9-null mice accumulating 10-20 times more arsenic than WT mice. Within hours after NaAsO2 injection, AQP9-null mice sustain profound bradycardia, despite normal serum electrolytes. Increased arsenic levels are also present in liver, lung, spleen, and testis of AQP9-null mice. Arsenic levels in the feces and urine of AQP9-null mice are only approximate to 10% of the WT levels, and reduced clearance of multiple arsenic species by the AQP9-null mice suggests that AQP9 is involved in the export of multiple forms of arsenic. Immunohistochemical staining of liver sections revealed that AQP9 is most abundant in basolateral membrane of hepatocytes adjacent to the sinusoids. AQP9 is not detected in heart or kidney by PCR or immunohistochemistry. We propose that AQP9 provides a route for excretion of arsenic by the liver, thereby providing partial protection of the whole animal from arsenic toxicity.