Involvement of Indoxyl Sulfate in Renal and Central Nervous System Toxicities During Cisplatin-induced Acute Renal Failure
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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.
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.
Key wordsacute renal failure AST-120 cisplatin indoxyl sulfate Per2
acute renal failure
chronic renal failure
central nervous system
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.
- 4.W. Lieberthal, V. Triaca, and J. Levine. Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis. Adv. Physiol. Educ. 270:700–708 (1996).Google Scholar
- 8.T. Miyazaki, M. Ise, H. Seo, and T., Niwa. Indoxyl sulfate increases the gene expression of TGF-beta 1, TIMP-1 and pro-α1(É) collagen in uremic rat kidneys. Kidney Inter., Suppl. 62:S15–S22 (1997).Google Scholar
- 9.T. Niwa, T. Nomura, S. Sugiyama, T. Miyazaki, S. Tsukushi, and S. Tsutsui. The protein metabolite hypothesis, a model for the progression of renal failure: an oral adsorbent lowers indoxyl sulfate levels in undialyzed uremic patients. Kidney Inter., Suppl. 62:S23–S28 (1997).Google Scholar
- 22.C. L. Robert, P. S. Richard, and C. Harold. The antitumor agent cis-Pt (NH3)2Cl2: distribution studies and dose calculation for 192mPt and 195mPt. J. Nucl. Med. 14:191–195 (1972).Google Scholar
- 31.S. Ohtsuki, H. Asaba, H. Takanaga, T. Deguchi, K. Hosoya, M. Otagiri, and T. Terasaki. Role of blood-brain barrier organic anion teansporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J. Neurochem. 83:57–66 (2002).PubMedCrossRefGoogle Scholar
- 36.C. K. Song, and T. J. Bartness. CNS sympathetic outflow neurons to white fat that express MEL receptors may mediate seasonal adiposity. Am. J. Physiol., Regul. Integr. Comp. Physiol. 281:R666–R672 (2001).Google Scholar
- 37.R. M. Buijs, S. J. Chun, A. Niijima, H. J. Romijn, and K. Nagai. Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J. Comp. Neurol. 431:405–423 (2001).PubMedCrossRefGoogle Scholar