SLCO4C1 Transporter Eliminates Uremic Toxins and Attenuates Hypertension and Renal Inflammation

被引：111

作者：

Toyohara, Takafumi ^{[2
]}

Suzuki, Takehiro ^{[2
]}

Morimoto, Ryo ^{[2
]}

Akiyama, Yasutoshi ^{[2
]}

Souma, Tomokazu ^{[2
]}

Shiwaku, Hiromi O. ^{[2
]}

Takeuchi, Yoichi ^{[2
]}

Mishima, Eikan ^{[2
]}

Abe, Michiaki ^{[2
]}

Tanemoto, Masayuki ^{[2
]}

Masuda, Satohiro ^{[6
]}

Kawano, Hiroaki ^{[7
]}

Maernura, Koji ^{[7
]}

Nakayama, Masaaki ^{[3
]}

Sato, Hiroshi ^{[2
]}

Mikkaichi, Tsuyoshi ^{[8
]}

Yamaguchi, Hiroaki ^{[8
]}

Fukui, Shigefumi ^{[4
]}

Fukumoto, Yoshihiro ^{[4
]}

Shimokawa, Hiroaki ^{[4
]}

Inui, Ken-ichi ^{[6
]}

Terasaki, Tetsuya ^{[9
]}

Goto, Junichi ^{[8
]}

Ito, Sadayoshi ^{[2
]}

Hishinuma, Takanori ^{[10
]}

Rubera, Isabelle ^{[11
]}

Tauc, Michel ^{[11
]}

Fujii-Kuriyama, Yoshiaki ^{[12
,13
,15
]}

Yabuuchi, Hikaru ^{[14
]}

Moriyama, Yoshinori

Soga, Tomoyoshi ^{[16
]}

Abe, Takaaki ^{[1
,5
]}

机构：

[1] Tohoku Univ, Div Med Sci, Grad Sch Biomed Engn, Sendai, Miyagi 9808574, Japan

[2] Tohoku Univ, Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi 9808574, Japan

[3] Tohoku Univ, Sch Med, Res Div Dialysis & Chron Kidney Dis, Sendai, Miyagi 9808574, Japan

[4] Tohoku Univ, Sch Med, Dept Cardiovasc Med, Sendai, Miyagi 9808574, Japan

[5] Tohoku Univ, Sch Med, Dept Clin Biol & Hormonal Regulat, Sendai, Miyagi 9808574, Japan

[6] Kyoto Univ, Fac Med, Dept Pharm, Kyoto Univ Hosp, Kyoto, Japan

[7] Nagasaki Univ, Sch Med, Dept Cardiovasc Med, Nagasaki 852, Japan

[8] Tohoku Univ Hosp, Dept Pharmaceut Sci, Sendai, Miyagi, Japan

[9] Tohoku Univ, Div Membrane Transport & Drug Targeting, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808574, Japan

[10] Tohoku Univ, Div Pharmacotherapy, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808574, Japan

[11] Univ Nice Sophia Antipolis, CNRS, FRE3093, Nice 2, France

[12] Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki, Japan

[13] Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan

[14] GenoMembrane Inc, Yokohama, Kanagawa, Japan

[15] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Membrane Biochem, Okayama, Japan

[16] Keio Univ, Inst Adv Biosci, Tsuruoka, Yamagata, Japan

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2009年 / 20卷 / 12期

基金：

日本科学技术振兴机构;

关键词：

ARYL-HYDROCARBON RECEPTOR; CHRONIC KIDNEY-DISEASE; ASYMMETRIC DIMETHYLARGININE; BLOOD-PRESSURE; FAILURE; HEMODIALYSIS; INVOLVEMENT; DEFICIENCY; ACTIVATION; INDUCTION;

D O I：

10.1681/ASN.2009070696

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

100201 [内科学]; 100221 [泌尿外科学];

摘要：

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.

引用

页码：2546 / 2555

页数：10

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