Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Kumamoto, Japan.
Clin Exp Nephrol. 2009 Dec;13(6):578-84. doi: 10.1007/s10157-009-0215-1. Epub 2009 Jul 24.
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.
本研究旨在探讨低镁血症对顺铂（CDDP）诱导的大鼠急性肾损伤（AKI）的影响，以及低镁血症与有机阳离子转运体的调节和 CDDP 在肾脏中的蓄积的关系。
在给予 CDDP 治疗前 7 天，SD 大鼠开始给予低镁饮食。CDDP 通过左颈静脉以 3mg/kg 的剂量分别给予正常镁饮食组和低镁饮食组大鼠静脉内给药。在注射 CDDP 后的指定时间段后，使用电感耦合等离子体质谱法测定血和器官样本中的铂含量。测定肾有机阳离子转运体的蛋白表达水平。测量大鼠肾切片中四乙基铵（TEA）溴化物的摄取。
与给予充足镁饮食的对照组大鼠相比，给予低镁饮食的大鼠体重明显下降，血清镁水平明显降低。在对照组大鼠中，CDDP 治疗后血清血尿素氮和肌酐水平没有改变，而低镁血症大鼠的这些水平明显升高。免疫印迹显示，在给予 CDDP 之前，低镁血症大鼠的有机阳离子转运体 rOCT2 上调，但 rOCT1 或大鼠多药和毒素外排 1 没有上调。低镁血症大鼠肾切片的 TEA 摄取明显高于对照组大鼠。低镁血症大鼠的 CDDP 在肾脏中的蓄积明显增加。
这些结果表明，低镁血症可引起脱水和 rOCT2 的上调，增强 CDDP 在肾脏中的蓄积和 AKI 的恶化。
