Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats
Enhanced renal accumulation of cisplatin via renal organic cation transporter deteriorates acute kidney injury in hypomagnesemic rats
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DOI：
10.1007/s10157-009-0215-1
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发表时间：
2009-12-01
影响因子：
2.3
通讯作者：
Saito, Hideyuki
中科院分区：
文献类型：
--
作者：
Yokoo, Koji;Murakami, Risa;Saito, Hideyuki
为探讨低镁血症对顺铂（CDDP）诱导的大鼠急性肾损伤（阿基）的影响及其与有机阳离子转运体调节和CDDP肾蓄积的关系，采用SD大鼠，在CDDP治疗前7天开始给予低镁饮食。正常镁饮食组和缺镁饮食组大鼠经左颈静脉给予CDDP 3 mg/kg。在注射CDDP后的指定时间段，使用电感耦合等离子体质谱法测定血液和器官样本中的铂量。测定肾脏有机阳离子转运蛋白的蛋白表达水平。测定了大鼠肾片对四乙基溴化铵（TEA）的摄取，结果表明，与正常对照组相比，缺镁组大鼠体重明显下降，血清镁水平明显降低。CDDP治疗后，对照组大鼠的血清尿素氮和肌酐水平没有改变，而这些水平在低镁血症大鼠中显著升高。免疫印迹显示CDDP给药前低镁血症大鼠有机阳离子转运蛋白rOCT 2上调，但rOCT 1或大鼠多药和毒素排出1未上调。低镁血症大鼠肾片对TEA的摄取明显高于对照组。低镁血症大鼠肾组织中CDDP蓄积明显增加，提示低镁血症可引起脱水和rOCT 2表达上调，促进CDDP在肾组织中蓄积，加重阿基。
This study aimed to explore the effects of hypomagnesemia on cisplatin (CDDP)-induced acute kidney injury (AKI) in rats and the relation of hypomagnesemia to the regulation of organic cation transporters and renal accumulation of CDDP.Sprague-Dawley rats were given an Mg-deficient diet starting 7 days before treatment with CDDP. CDDP was administered intravenously to rats in the normal Mg-diet group and Mg-deficient-diet group at 3 mg/kg via the left jugular vein. At the specified periods after injection of CDDP, the amount of platinum in blood and organ samples was determined using inductively coupled plasma-mass spectrometry. Protein expression levels of renal organic cation transporters were determined. Uptake of tetraethylammonium (TEA) bromide in renal slices of rats was measured.Rats fed a Mg-deficient diet showed a significant body weight decrease and a marked decrease in serum Mg levels compared with control rats fed an adequate Mg diet. Serum blood urea nitrogen and creatinine levels were unaltered after CDDP treatment in control rats, whereas these levels were markedly elevated in hypomagnesemic rats. Immunoblotting revealed up-regulation of the organic cation transporter rOCT2 in hypomagnesemic rats before CDDP administration, but not of rOCT1 or rat multidrug and toxin-extrusion 1. TEA uptake by renal slices from hypomagnesemic rats was significantly higher compared with that of control rats. Renal accumulation of CDDP was markedly increased in hypomagnesemic rats.These results suggest that hypomagnesemia could cause dehydration and up-regulation of rOCT2, enhancing renal accumulation of CDDP and the deterioration of AKI.