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Involvement of Indoxyl Sulfate in Renal and Central Nervous System Toxicities During Cisplatin-induced Acute Renal Failure

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Purpose

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.

Materials and Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

IS:

indoxyl sulfate

ARF:

acute renal failure

CRF:

chronic renal failure

SCN:

suprachiasmatic nucleus

CNS:

central nervous system

ZT:

zeitgeber time

Per2 :

period 2

SCr:

serum creatinine

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Acknowledgments

This work was supported, in part, by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

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Authors and Affiliations

  1. Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, 860-8556, Japan

    Kazufumi Iwata, Hiroshi Watanabe, Takafumi Morisaki, Takanobu Matsuzaki, Takafumi Ohmura,  Akinobu Hamada & Hideyuki Saito

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  1. Kazufumi Iwata
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  2. Hiroshi Watanabe
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  3. Takafumi Morisaki
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  4. Takanobu Matsuzaki
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Correspondence to Hideyuki Saito.

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K.I. and H.W. contributed equally to this work.

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Iwata, K., Watanabe, H., Morisaki, T. et al. Involvement of Indoxyl Sulfate in Renal and Central Nervous System Toxicities During Cisplatin-induced Acute Renal Failure. Pharm Res 24, 662–671 (2007). https://doi.org/10.1007/s11095-006-9183-2

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  • DOI: https://doi.org/10.1007/s11095-006-9183-2

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