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This Article Full Text Full Text (PDF) All Versions of this Article: 292/6/F1819    most recent 00017.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Ogasawara, K. Articles by Inui, K.-i. Search for Related Content PubMed PubMed Citation Articles by Ogasawara, K. Articles by Inui, K.-i.

Hepatocyte nuclear factor-4 regulates the human organic anion transporter 1 gene in the kidney

Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan

Submitted 10 January 2007 ; accepted in final form 1 March 2007

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. An electrophoretic mobility shift assay showed that HNF-4 bound to DR-2 and IR-8 under the conditions of HNF-4 overexpression. 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.

SLC22A6; proximal tubule; promoter; inverted repeat-8

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