MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice
MRP-1 expression levels determine strain-specific susceptibility to sodium arsenic-induced renal injury between C57BL/6 and BALB/c mice
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DOI：
10.1016/j.taap.2004.07.013
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发表时间：
2005-02-15
影响因子：
3.8
通讯作者：
Kondo, T
中科院分区：
文献类型：
--
作者：
Kimura, A;Ishida, Y;Kondo, T
为了阐明砷急性暴露引起急性肾损伤的病理生理机制，我们给BALB/c和C57 BL/6小鼠皮下注射亚砷酸钠（NaAs; 13.5 mg/kg）。与C57 BL/6小鼠相比，BALB/c小鼠表现出血清尿素氮（BUN）和肌酐（CRE）水平的过度升高。此外，半数BALB/c小鼠在24 h内死亡，而所有C57 BL/6小鼠均存活。BALB/c小鼠肾脏组织病理学检查显示，PAS阳性刷状缘消失，肾小管坏死，中性粒细胞浸润，管型形成。与BALB/c小鼠相比，C57 BL/6小鼠的这些病理变化明显减轻，同时肾内砷浓度较低。在重金属诱导蛋白中，包括多药耐药相关蛋白（MRP）-1、多药耐药基因（MDR）-1、金属硫蛋白（MT）-1和亚砷酸盐诱导蛋白，富含半胱氨酸和组氨酸的RNA相关蛋白（AIRAP）、肾内MDR-1、MT-1和AIRAP基因表达在两种菌株中增强到相似的程度，而NaAs刺激可增加C57 BL/6小鼠肾内MRP-1 mRNA和蛋白表达水平，但对BALB/c小鼠无影响。此外，MRP-1的特异性抑制剂MK-571的给药显著加重了C57 BL/6小鼠的急性肾损伤。因此，MRP-1是至关重要的参与砷流出，并最终预防急性肾损伤后，急性暴露于砷。(C)2004爱思唯尔公司All rights reserved.
To clarify the pathophysiological mechanism underlying acute renal injury caused by acute exposure to arsenic, we subcutaneously injected both BALB/c and C57BL/6 mice with sodium arsenite (NaAs; 13.5 mg/kg). BALB/c mice exhibited exaggerated elevation of serum blood urea nitrogen (BUN) and creatinine (CRE) levels, compared with C57BL/6 mice. Moreover, half of BALB/c mice died by 24 h, whereas all C57BL/6 mice survived. Histopathological examination on kidney revealed severe hemorrhages, acute tubular necrosis, neutrophil infiltration, cast formation, and disappearance of PAS-positive brush borders in BALB/c mice, later than 10 h. These pathological changes were remarkably attenuated in C57BL/6 mice, accompanied with lower intrarenal arsenic concentrations, compared with BALB/c mice. Among heavy metal inducible proteins including multidrug resistance-associated protein (MRP)-1, multidrug resistance gene (MDR)-1, metallothionein (MT)-1, and arsenite inducible, cysteine- and histidine-rich RNA-associated protein (AIRAP), intrarenal MDR-1, MT-1, and AIRAP gene expression was enhanced to a similar extent in both strains, whereas NaAs challenge augmented intrarenal MRP-1 mRNA and protein expression levels in C57BL/6 but not BALB/c mice. Moreover, the administration of a specific inhibitor of MRP-1, MK-571, significantly exaggerated acute renal injury in C57BL/6 mice. Thus, MRP-1 is crucially involved in arsenic efflux and eventually prevention of acute renal injury upon acute exposure to NaAs. (C) 2004 Elsevier Inc. All rights reserved.