title: Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure.
abstract: 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.
authors.affiliation: Department of Pharmacy, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Iwata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Takafumi
authors.initials: T
authors.lastname: Morisaki
authors.forename: Takanobu
authors.initials: T
authors.lastname: Matsuzaki
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ohmura
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saito
mesh_terms: 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
chemical_list: 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