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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: ASN.2009070696v1 ASN.2009070696v2 20/12/2546    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Toyohara, T. Articles by Abe, T. Search for Related Content PubMed PubMed Citation Articles by Toyohara, T. Articles by Abe, T. Related Collections Related Articles

SLCO4C1 Transporter Eliminates Uremic Toxins and Attenuates Hypertension and Renal Inflammation

Takafumi Toyohara^*, Takehiro Suzuki^*, Ryo Morimoto^*, Yasutoshi Akiyama^*, Tomokazu Souma^*, Hiromi O. Shiwaku^*, Yoichi Takeuchi^*, Eikan Mishima^*, Michiaki Abe^*, Masayuki Tanemoto^*, Satohiro Masuda, Hiroaki Kawano, Koji Maemura, Masaaki Nakayama, Hiroshi Sato^*, Tsuyoshi Mikkaichi^||, Hiroaki Yamaguchi^||, Shigefumi Fukui^¶, Yoshihiro Fukumoto^¶, Hiroaki Shimokawa^¶, Ken-ichi Inui, Tetsuya Terasaki^**, Junichi Goto^||, Sadayoshi Ito^*, Takanori Hishinuma, Isabelle Rubera, Michel Tauc, Yoshiaki Fujii-Kuriyama, Hikaru Yabuuchi^||||, Yoshinori Moriyama^¶¶, Tomoyoshi Soga^*** and Takaaki Abe^*,,

*Division of Nephrology, Endocrinology, and Vascular Medicine,
Research Division of Dialysis and Chronic Kidney Disease,
^¶Department of Cardiovascular Medicine, and
Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan;
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan;
Department of Cardiovascular Medicine, Nagasaki University School of Medicine, Nagasaki, Japan;
^||Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan;
**Division of Membrane Transport and Drug Targeting and
Division of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan;
CNRS-FRE3093, University of Nice-Sophia Antipolis, Parc Valrose, Nice Cedex 2, France;
Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan;
^||||GenoMembrane Inc., Yokohama, Japan;
^¶¶Department of Membrane Biochemistry, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
***Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan; and
Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan

Correspondence: Dr. Takaaki Abe, Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai 980-8574 Japan. Phone: +81-22-717-7163; Fax: +81-22-717-7168; E-mail: takaabe{at}mail.tains.tohoku.ac.jp; or Dr. Takehiro Suzuki, Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seriyo-cho, Aoba-ku, Sendai 980-8574, Japan. Phone: +81-22-717-7163; Fax: +81-22-717-7168; E-mail: suzuki2i{at}mail.tains.tohoku.ac.jp

Received for publication July 3, 2009. Accepted for publication September 9, 2009.

Hypertension in patients with chronic kidney disease (CKD) strongly associates with cardiovascular events. Among patients with CKD, reducing the accumulation of uremic toxins may protect against the development of hypertension and progression of renal damage, but there are no established therapies to accomplish this. Here, overexpression of human kidney-specific organic anion transporter SLCO4C1 in rat kidney reduced hypertension, cardiomegaly, and inflammation in the setting of renal failure. In addition, SLCO4C1 overexpression decreased plasma levels of the uremic toxins guanidino succinate, asymmetric dimethylarginine, and the newly identified trans-aconitate. We found that xenobiotic responsive element core motifs regulate SLCO4C1 transcription, and various statins, which act as inducers of nuclear aryl hydrocarbon receptors, upregulate SLCO4C1 transcription. Pravastatin, which is cardioprotective, increased the clearance of asymmetric dimethylarginine and trans-aconitate in renal failure. These data suggest that drugs that upregulate SLCO4C1 may have therapeutic potential for patients with CKD.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673