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Regulation of Renal Organic Ion Transporters in Cisplatin-Induced Acute Kidney Injury and Uremia in Rats

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The purpose of this study was to examine the regulation of renal organic ion transporters in cisplatin-induced acute kidney injury (AKI) and its relation with indoxyl sulfate (IS), a uremic toxin.


The IS concentrations in the serum and kidney were monitored by high-performance liquid chromatography. Uptake of p-aminohippuric acid, estrone-3-sulfate and tetraethylammonium were examined using renal slices. Real-time PCR and immunoblotting were performed to examine the mRNA and protein expression of rOATs, rOCTs and rMATE1 in the kidney, respectively.


The serum and renal IS levels were markedly elevated in cisplatin-treated rats. However, this effect was largely reversed by administration of AST-120, an oral charcoal adsorbent. The functions of renal basolateral organic anion and cation transporters were reduced in cisplatin-treated rats. The levels of mRNA and protein corresponding to rOAT1, rOAT3, rOCT2 and rMATE1, but not rOCT1, were depressed in the kidney of cisplatin-treated rats. Administration of AST-120 to cisplatin-treated rats partially restored the function and expression level of these transporters.


Cisplatin-induced AKI causes down-regulation of renal organic ion transporters accompanied by accumulation of serum and renal IS. IS could be involved in the mechanism of down-regulation of rOAT1, rOAT3 and rMATE1 under cisplatin-induced AKI.

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acute kidney injury


blood urea nitrogen




indoxyl sulfate


multidrug and toxin extrusion


organic anion transporter


organic cation transporter


p-aminohippuric acid


serum creatinine




  1. R. W. Schrier. Cancer therapy and renal injury. J. Clin. Invest. 110:743–745 (2002).

    PubMed  CAS  Google Scholar 

  2. F. E. de Jongh, R. N. van Veen, S. J. Veltman, R. de Wit, M. E. van der Burg, M. J. van den Bent, A. S. Planting, W. J. Graveland, G. Stoter, and J. Verweij. Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients. Br. J. Cancer. 88:1199–1206 (2003). doi:10.1038/sj.bjc.6600884.

    Article  PubMed  Google Scholar 

  3. X. Yao, K. Panichpisal, N. Kurtzman, and K. Nugent. Cisplatin nephrotoxicity: a review. Am. J. Med. Sci. 334:115–124 (2007). doi:10.1097/MAJ.0b013e31812dfe1e.

    Article  PubMed  Google Scholar 

  4. K. Iwata, H. Watanabe, T. Morisaki, T. Matsuzaki, T. Ohmura, A. Hamada, and H. Saito. Involvement of indoxyl sulfate in renal and central nervous system toxicities during cisplatin-induced acute renal failure. Pharm. Res. 24:662–671 (2007). doi:10.1007/s11095-006-9183-2.

    Article  PubMed  CAS  Google Scholar 

  5. T. Niwa, and M. Ise. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J. Lab. Clin. Med. 124:96–104 (1994).

    PubMed  CAS  Google Scholar 

  6. T. Deguchi, S. Ohtsuki, M. Otagiri, H. Takanaga, H. Asaba, S. Mori, and T. Terasaki. Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int. 61:1760–1768 (2002). doi:10.1046/j.1523-1755.2002.00318.x.

    Article  PubMed  CAS  Google Scholar 

  7. A. Enomoto, M. Takeda, A. Tojo, T. Sekine, S. H. Cha, S. Khamdang, F. Takayama, I. Aoyama, S. Nakamura, H. Endou, and T. Niwa. Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J. Am. Soc. Nephrol. 13:1711–1720 (2002). doi:10.1097/01.ASN.0000022017.96399.B2.

    Article  PubMed  CAS  Google Scholar 

  8. T. Miyazaki, I. Aoyama, M. Ise, H. Seo, and T. Niwa. An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys. Nephrol. Dial. Transplant. 15:1773–1781 (2000). doi:10.1093/ndt/15.11.1773.

    Article  PubMed  CAS  Google Scholar 

  9. T. Niwa, S. Tsukushi, M. Ise, T. Miyazaki, Y. Tsubakihara, A. Owada, and T. Shiigai. Indoxyl sulfate and progression of renal failure: effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients. Miner. Electrolyte Metab. 23:179–184 (1997).

    PubMed  CAS  Google Scholar 

  10. K. Inui, S. Masuda, and H. Saito. Cellular and molecular aspects of drug transport in the kidney. Kidney Int. 58:944–958 (2000). doi:10.1046/j.1523-1755.2000.00251.x.

    Article  PubMed  CAS  Google Scholar 

  11. J. B. Pritchard, and D. S. Miller. Renal secretion of organic anions and cations. Kidney Int. 49:1649–1654 (1996). doi:10.1038/ki.1996.240.

    Article  PubMed  CAS  Google Scholar 

  12. D. Gründemann, V. Gorboulev, S. Gambaryan, M. Veyhl, and H. Koepsell. Drug excretion mediated by a new prototype of polyspecific transporter. Nature. 372:549–552 (1994). doi:10.1038/372549a0.

    Article  PubMed  Google Scholar 

  13. H. Kusuhara, T. Sekine, N. Utsunomiya-Tate, M. Tsuda, R. Kojima, S. H. Cha, Y. Sugiyama, Y. Kanai, and H. Endou. Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J. Biol. Chem. 274:13675–13680 (1999). doi:10.1074/jbc.274.19.13675.

    Article  PubMed  CAS  Google Scholar 

  14. M. Okuda, H. Saito, Y. Urakami, M. Takano, and K. Inui. cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem. Biophys. Res. Commun. 224:500–507 (1996). doi:10.1006/bbrc.1996.1056.

    Article  PubMed  CAS  Google Scholar 

  15. T. Sekine, N. Watanabe, M. Hosoyamada, Y. Kanai, and H. Endou. Expression cloning and characterization of a novel multispecific organic anion transporter. J. Biol. Chem. 272:18526–18529 (1997). doi:10.1074/jbc.272.30.18526.

    Article  PubMed  CAS  Google Scholar 

  16. T. Deguchi, M. Takemoto, N. Uehara, W. E. Lindup, A. Suenaga, and M. Otagiri. Renal clearance of endogenous hippurate correlates with expression levels of renal organic anion transporters in uremic rats. J. Pharmacol. Exp. Ther. 314:932–938 (2005). doi:10.1124/jpet.105.085613.

    Article  PubMed  CAS  Google Scholar 

  17. K. Y. Ohta, K. Inoue, Y. Hayashi, and H. Yuasa. Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H + antiporter in the kidney. Drug Metab. Dispos. 34:1868–1874 (2006). doi:10.1124/dmd.106.010876.

    Article  PubMed  CAS  Google Scholar 

  18. M. Otsuka, T. Matsumoto, R. Morimoto, S. Arioka, H. Omote, and Y. Moriyama. A human transporter protein that mediates the final excretion step for toxic organic cations. Proc. Natl. Acad. Sc.i U. S. A. 102:17923–17928 (2005). doi:10.1073/pnas.0506483102.

    Article  CAS  Google Scholar 

  19. T. Terada, S. Masuda, J. Asaka, M. Tsuda, T. Katsura, and K. Inui. Molecular cloning, functional characterization and tissue distribution of rat H + /organic cation antiporter MATE1. Pharm. Res. 23:1696–1701 (2006). doi:10.1007/s11095-006-9016-3.

    Article  PubMed  CAS  Google Scholar 

  20. L. Ji, S. Masuda, H. Saito, and K. Inui. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 62:514–524 (2002). doi:10.1046/j.1523-1755.2002.00464.x.

    Article  PubMed  CAS  Google Scholar 

  21. T. Matsuzaki, T. Morisaki, W. Sugimoto, K. Yokoo, D. Sato, H. Nonoguchi, K. Tomita, T. Terada, K. I. Inui, A. Hamada, and H. Saito. Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rOCT2 (Slc22a2) and rMATE1 (Slc47a1) in ischemia/reperfusion-induced acute kidney injury. Drug Metab. Dispos. 36:649–654 (2008).

    Article  Google Scholar 

  22. T. Matsuzaki, H. Watanabe, K. Yoshitome, T. Morisaki, A. Hamada, H. Nonoguchi, Y. Kohda, K. Tomita, K. Inui, and H. Saito. Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute renal failure. Kidney Int. 71:539–547 (2007). doi:10.1038/

    Article  PubMed  CAS  Google Scholar 

  23. K. Nishihara, S. Masuda, L. Ji, T. Katsura, and K. Inui. Pharmacokinetic significance of luminal multidrug and toxin extrusion 1 in chronic renal failure rats. Biochem. Pharmacol. 73:1482–1490 (2007). doi:10.1016/j.bcp.2006.12.034.

    Article  PubMed  CAS  Google Scholar 

  24. T. Sato, S. Miyazaki, and S. Mohri. Effects of an oral adsorbent on cisplatin-induced nephropathy in rats. Nippon Jinzo Gakkai Shi. 38:290–295 (1996).

    PubMed  CAS  Google Scholar 

  25. Y. K. Kim, H. S. Byun, Y. H. Kim, J. S. Woo, and S. H. Lee. Effect of cisplatin on renal function in rabbits: mechanism of reduced glucose reabsorption. Toxicol. Appl. Pharmacol. 130:19–26 (1995). doi:10.1006/taap.1995.1003.

    Article  PubMed  CAS  Google Scholar 

  26. D. H. Sweet. Organic anion transporter (Slc22a) family members as mediators of toxicity. Toxicol. Appl. Pharmacol. 204:198–215 (2005). doi:10.1016/j.taap.2004.10.016.

    Article  PubMed  CAS  Google Scholar 

  27. S. H. Wright, and W. H. Dantzler. Molecular and cellular physiology of renal organic cation and anion transport. Physiol. Rev. 84:987–1049 (2004). doi:10.1152/physrev.00040.2003.

    Article  PubMed  CAS  Google Scholar 

  28. C. Sauvant, H. Holzinger, and M. Gekle. Prostaglandin E2 inhibits its own renal transport by downregulation of organic anion transporters rOAT1 and rOAT3. J. Am. Soc. Nephrol. 17:46–53 (2006). doi:10.1681/ASN.2005070727.

    Article  PubMed  CAS  Google Scholar 

  29. M. Matsuyama, R. Yoshimura, T. Hase, Y. Kawahito, H. Sano, and T. Nakatani. Study of cyclooxygenase-2 in renal ischemia-reperfusion injury. Transplant Proc. 37:370–372 (2005). doi:10.1016/j.transproceed.2004.12.246.

    Article  PubMed  CAS  Google Scholar 

  30. Y. Urakami, M. Okuda, H. Saito, and K. Inui. Hormonal regulation of organic cation transporter OCT2 expression in rat kidney. FEBS Lett. 473:173–176 (2000). doi:10.1016/S0014-5793(00)01525-8.

    Article  PubMed  CAS  Google Scholar 

  31. Y. Masubuchi, M. Kawasaki, and T. Horie. Down-regulation of hepatic cytochrome P450 enzymes associated with cisplatin-induced acute renal failure in male rats. Arch. Toxicol. 80:347–353 (2006). doi:10.1007/s00204-006-0079-z.

    Article  PubMed  CAS  Google Scholar 

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This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) for Hideyuki Saito (KAKENHI 17390158) and Akinobu Hamada (KAKENHI 19590149).

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Correspondence to Hideyuki Saito.

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Morisaki, T., Matsuzaki, T., Yokoo, K. et al. Regulation of Renal Organic Ion Transporters in Cisplatin-Induced Acute Kidney Injury and Uremia in Rats. Pharm Res 25, 2526–2533 (2008).

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