Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure.
OBJECTIVE
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.


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.
Iwata
Kazufumi
K
Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, Japan.
Watanabe
Hiroshi
H
Morisaki
Takafumi
T
Matsuzaki
Takanobu
T
Ohmura
Takafumi
T
Hamada
Akinobu
A
Saito
Hideyuki
H
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents; D001806:Blood Urea Nitrogen; D001831:Body Temperature; D001835:Body Weight; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D002244:Carbon / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002493:Central Nervous System Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002940:Circadian Rhythm; D002945:Cisplatin; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005765:Gastrointestinal Agents / Q000494:pharmacology; D015870:Gene Expression; D007200:Indican / Q000097:blood / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D056950:Period Circadian Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013493:Suprachiasmatic Nucleus / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D005765:Gastrointestinal Agents; D009687:Nuclear Proteins; D010087:Oxides; C513311:Per2 protein, rat; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D002244:Carbon; C040896:AST 120; D003404:Creatinine; D007200:Indican; D002945:Cisplatin