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First published on September 13, 2007; DOI: 10.1124/mol.107.039701

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Received for publication July 6, 2007.
Revised August 30, 2007.
Accepted for publication September 10, 2007.

Regulation of Tissue-Specific Expression of the Human and Mouse Urate Transporter 1 Gene by Hepatocyte Nuclear Factor 1 {alpha}/{beta} and DNA Methylation

Ryota Kikuchi 1, Hiroyuki Kusuhara 1, Naka Hattori 1, Insook Kim 2, Kunio Shiota 1, Frank J. Gonzalez 2, Yuichi Sugiyama 1*

1 The University of Tokyo 2 NCI, NIH

* Address correspondence to: E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

Abstract

Expression of Urate transporter 1 (URAT1/SLC22A12) is restricted to the proximal tubules in the kidney, where it is responsible for the tubular reabsorption of urate. In order to elucidate the mechanism underlying its tissue-specific expression, the transcriptional regulation of the hURAT1 and mUrat1 genes was investigated. Hepatocyte Nuclear Factor 1 {alpha} (HNF1{alpha}) and HNF1{beta} positively regulate minimal promoter activity of the URAT1 gene as shown by reporter gene assays. Electrophoretic mobility shift assays revealed binding of HNF1{alpha} and/or HNF1{beta} to the HNF1-motif in the hURAT1 promoter. Furthermore, the mRNA expression of Urat1 is reduced in the kidneys of Hnf1{alpha}-null mice compared with wild-type mice, confirming the indispensable role of HNF1{alpha} in the constitutive expression of URAT1 genes. It was also shown that the proximal promoter region of mUrat1 was hypermethylated in the liver and kidney medulla, whereas this region was relatively hypomethylated in the kidney cortex. These methylation profiles are in a good agreement with the proximal tubule-restricted expression of mUrat1 in the kidney cortex. Taken together, these results strongly suggest that tissue-specific expression of the URAT1 genes is coordinately regulated by the transcriptional activation by HNF1{alpha}/HNF1{beta} heterodimer and repression by DNA methylation.


Key words: Promoter analysis, Organic anion, Regulation of gene expression, Regulation - transcriptional


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