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 ShimokawaKen Ichi Inui, Tetsuya Terasaki, Junichi Goto, Sadayoshi Ito, Takanori Hishinuma, Isabelle Rubera, Michel Tauc, Yoshiaki Fujii-Kuriyama, Hikaru Yabuuchi, Yoshinori Moriyama, Tomoyoshi Soga, Takaaki Abe

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Abstract

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.

Original languageEnglish
Pages (from-to)2546-2555
Number of pages10
JournalJournal of the American Society of Nephrology
Volume20
Issue number12
DOIs
Publication statusPublished - 2009 Dec 1

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ASJC Scopus subject areas

  • Nephrology

Cite this

Toyohara, T., Suzuki, T., Morimoto, R., Akiyama, Y., Souma, T., Shiwaku, H. O., Takeuchi, Y., Mishima, E., Abe, M., Tanemoto, M., Masuda, S., Kawano, H., Maemura, K., Nakayama, M., Sato, H., Mikkaichi, T., Yamaguchi, H., Fukui, S., Fukumoto, Y., ... Abe, T. (2009). SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. Journal of the American Society of Nephrology, 20(12), 2546-2555. https://doi.org/10.1681/ASN.2009070696