Transcriptional Regulation of Human and Mouse Organic Anion Transporter 1 by Hepatocyte Nuclear Factor 1 α/β

Authors:
  • RKRyota Kikuchi
    Ryota Kikuchi
  • HKHiroyuki Kusuhara
    Hiroyuki Kusuhara
  • IKInsook Kim
    Insook Kim
  • FGFrank J. Gonzalez
    Frank J. Gonzalez
  • YSYuichi Sugiyama
    Yuichi Sugiyama
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Abstract
Organic anion transporter 1 (OAT1/SLC22A6) is predominantly expressed in the proximal tubules of the kidney. Cumulative studies have shown its critical role in the tubular secretion of a variety of organic anions, including several clinically important drugs. In addition, OAT1 is also involved in the pharmacological effect of diuretics and the nephrotoxicity of antiviral drugs. In contrast to these functional characterizations, the regulatory mechanism of OAT1 expression is poorly understood. It was recently demonstrated that the expression of Oat1 was markedly reduced in the kidneys of hepatocyte nuclear factor 1α (Hnf1α)-null mice. However, in vitro evidence for the involvement of HNF1α and further analyses are required to illustrate the transcriptional regulation of OAT1 genes in more detail. Computational analysis of the potential transcription factor binding sites revealed that the HNF1-motif was conserved in the proximal-promoter region of human and mouse OAT1 genes. The mRNA expression of mouse organic anion transporter 1 was drastically reduced in Hnf1α-null mice compared with that in wild-type mice, which was consistent with a previous report (Maher et al., 2006). Forced expression of HNF1α alone or both HNF1α and HNF1β enhanced the activity of human and mouse OAT1 promoters in the transactivation assays, whereas HNF1β alone was not active. Mutations in the HNF1-motif significantly reduced this transactivation. Direct binding of HNF1α/HNF1α homodimer and HNF1α/HNF1β heterodimer to the HNF1-motif found in the human OAT1 promoter was demonstrated by electrophoretic mobility shift assays. These results provide convincing evidence for the involvement of HNF1α/β in the constitutive expression of human and mouse OAT1 in the kidney.

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