Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure
Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure
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DOI：
10.1007/s11095-006-9183-2
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发表时间：
2007-04-01
影响因子：
3.7
通讯作者：
Saito, Hideyuki
中科院分区：
文献类型：
--
作者：
Iwata, Kazufumi;Watanabe, Hiroshi;Saito, Hideyuki
本研究旨在探讨硫酸吲哚酚（indoxyl sulfate，IS）对顺铂（cisplatin，CDDP）所致大鼠肾毒性和中枢神经系统（central nervous system，CNS）毒性的影响。采用高效液相色谱法测定血清、脑和肾组织中IS的含量。监测体重和直肠温度。实时荧光定量PCR检测肾组织中rPer 2 mRNA的表达。CDDP治疗后24-84 h，血清、脑和肾中IS浓度明显升高。同时给予AST-120可抑制血清肌酐、BUN和IS水平的升高。CDDP治疗后72-92 h直肠温度显著降低，AST-120联合给药可部分恢复。此外，直肠温度节律的幅度被CDDP治疗破坏。CDDP处理后，大鼠视交叉上核（SCN）和肾脏的生物钟基因rPer 2 mRNA表达的昼夜节律紊乱，IS水平的升高及其相关的昼夜节律紊乱与CDDP处理后的肾脏和中枢神经系统毒性有关。
The purpose of the present study was to explore the involvement of indoxyl sulfate (IS) in nephrotoxicity and central nervous system (CNS) toxicity in cisplatin (CDDP)-treated rats.Renal function was evaluated by serum creatinine and BUN levels. The IS levels in the serum, brain and kidney was monitored by high-performance liquid chromatography method. Body weight and rectal temperature were monitored. Real-time PCR analysis was performed to examine rPer2 mRNA expression.Renal function deteriorated in a time-dependent manner after administration of CDDP. The concentration of IS in the serum, brain and kidney markedly increased 24-84 h after commencement of CDDP treatment. The observed increase in the levels of serum creatinine, BUN and IS was suppressed by concomitant administration of AST-120. Rectal temperature was significantly lowered 72-92 h after CDDP-treatment, which was partially restored by coadministration of AST-120. Moreover, the amplitude of rectal temperature rhythms was disrupted by treatment with CDDP. Circadian rhythm of rPer2 mRNA expression, a clock gene, in suprachiasmatic nucleus (SCN) and kidney was disturbed in CDDP-treated rats.An increase in the IS level and the associated disturbance to the circadian rhythm are involved in the renal and CNS toxicities in CDDP-treatment.