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regulates the human organic anion transporter 1 gene in the kidney
1 Department of Pharmacy, Kyoto University Hospital, Kyoto , Kyoto, Japan
2 Department of Pharmacy, Kyoto University Hospital, Kyoto , Japan
3 Kyoto, Japan; Department of Pharmacy, Kyoto University Hospital, Kyoto , Kyoto, Japan
* To whom correspondence should be addressed. E-mail: inui{at}kuhp.kyoto-u.ac.jp.
Human organic anion transporter 1 (OAT1, SLC22A6), which is localized to the basolateral membranes of renal tubular epithelial cells, plays a critical role in the excretion of anionic compounds. OAT1 is regulated by various pathophysiological conditions, but little is known about the molecular mechanisms regulating the expression of OAT1. In the present study, we investigated the transcriptional regulation of OAT1 and found that hepatocyte nuclear factor (HNF)-4
markedly transactivated the OAT1 promoter. A deletion analysis of the OAT1 promoter suggested that the regions spanning -1191 to -700 base pairs (bp) and -140 to -79 bp were essential for the transactivation by HNF-4. These regions contained a direct repeat separated by two nucleotides (DR-2), which is one of the consensus sequences binding to HNF-4, and an inverted repeat separated by eight nucleotides (IR-8), which was recently identified as a novel element for HNF-4, respectively. Electrophoretic mobility shift assay showed that HNF-4 bound to DR-2 and IR-8 under the conditions of HNF-4 over-expression. Furthermore, under normal conditions, HNF-4 bound to IR-8, and a mutation in IR-8 markedly reduced the OAT1 promoter activity, indicating that HNF-4 regulates the basal transcription of OAT1 via IR-8. This paper reports the first characterization of the human OAT1 promoter and the first gene in the kidney whose promoter activity is regulated by HNF-4.
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