SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation.

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.

• Authors: 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, Takaaki Abe
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 20 Issue 12 Pg. 2546-55 (Dec 2009) ISSN: 1533-3450 [Electronic] United States
• PMID: 19875811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Organic Anion Transporters
• Recombinant Proteins
• SLCO4C1 protein, human
• Toxins, Biological
• uremia middle molecule toxins
• DNA

Topics

• Animals
• Animals, Genetically Modified
• Base Sequence
• Biological Transport, Active
• DNA (genetics)
• Gene Expression
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hypertension (drug therapy, genetics, metabolism)
• Male
• Models, Biological
• Molecular Sequence Data
• Nephritis (drug therapy, genetics, metabolism)
• Organic Anion Transporters (genetics, metabolism)
• Promoter Regions, Genetic
• Rats
• Recombinant Proteins (genetics, metabolism)
• Renal Insufficiency, Chronic (drug therapy, genetics, metabolism)
• Toxins, Biological (metabolism)
• Uremia (drug therapy, metabolism)