title: 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.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Toyohara
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ryo
authors.initials: R
authors.lastname: Morimoto
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Souma
authors.forename: Hiromi O
authors.initials: HO
authors.lastname: Shiwaku
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Eikan
authors.initials: E
authors.lastname: Mishima
authors.forename: Michiaki
authors.initials: M
authors.lastname: Abe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanemoto
authors.forename: Satohiro
authors.initials: S
authors.lastname: Masuda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kawano
authors.forename: Koji
authors.initials: K
authors.lastname: Maemura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Fukui
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimokawa
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Inui
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
authors.forename: Junichi
authors.initials: J
authors.lastname: Goto
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.forename: Takanori
authors.initials: T
authors.lastname: Hishinuma
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Fujii-Kuriyama
authors.forename: Hikaru
authors.initials: H
authors.lastname: Yabuuchi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Moriyama
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001693:Biological Transport, Active; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009393:Nephritis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D014118:Toxins, Biological / Q000378:metabolism*; D014511:Uremia / Q000188:drug therapy / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D011994:Recombinant Proteins; C484530:SLCO4C1 protein, human; D014118:Toxins, Biological; C026865:uremia middle molecule toxins; D004247:DNA