SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation.
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.
Toyohara
Takafumi
T
Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan.
Suzuki
Takehiro
T
Morimoto
Ryo
R
Akiyama
Yasutoshi
Y
Souma
Tomokazu
T
Shiwaku
Hiromi O
HO
Takeuchi
Yoichi
Y
Mishima
Eikan
E
Abe
Michiaki
M
Tanemoto
Masayuki
M
Masuda
Satohiro
S
Kawano
Hiroaki
H
Maemura
Koji
K
Nakayama
Masaaki
M
Sato
Hiroshi
H
Mikkaichi
Tsuyoshi
T
Yamaguchi
Hiroaki
H
Fukui
Shigefumi
S
Fukumoto
Yoshihiro
Y
Shimokawa
Hiroaki
H
Inui
Ken-ichi
K
Terasaki
Tetsuya
T
Goto
Junichi
J
Ito
Sadayoshi
S
Hishinuma
Takanori
T
Rubera
Isabelle
I
Tauc
Michel
M
Fujii-Kuriyama
Yoshiaki
Y
Yabuuchi
Hikaru
H
Moriyama
Yoshinori
Y
Soga
Tomoyoshi
T
Abe
Takaaki
T
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
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