QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.039701v1 72/6/1619    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal 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 Google Scholar Google Scholar Articles by Kikuchi, R. Articles by Sugiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Kikuchi, R. Articles by Sugiyama, Y.

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

Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (R.K., H.K., Y.S.); Laboratory of Cellular Biochemistry, Department of Animal Resource Sciences/Veterinary Medical Sciences, the University of Tokyo, Tokyo, Japan (N.H., K.S.); Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (I.K., F.J.G.)

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. To elucidate the mechanism underlying its tissue-specific expression, the transcriptional regulation of the hURAT1 and mUrat1 genes was investigated. Hepatocyte nuclear factor 1 (HNF1) and HNF1 positively regulate minimal promoter activity of the URAT1 gene as shown by reporter gene assays. Electrophoretic mobility shift assays revealed binding of HNF1 and/or HNF1 to the HNF1 motif in the hURAT1 promoter. Furthermore, the mRNA expression of Urat1 is reduced in the kidneys of Hnf1-null mice compared with wild-type mice, confirming the indispensable role of HNF1 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/HNF1 heterodimer and repression by DNA methylation.

Address correspondence to: Dr. Yuichi Sugiyama, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

This article has been cited by other articles:

				M. Aoki, T. Terada, M. Kajiwara, K. Ogasawara, I. Ikai, O. Ogawa, T. Katsura, and K.-i. Inui Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation Am J Physiol Renal Physiol, July 1, 2008; 295(1): F165 - F170. [Abstract] [Full Text] [PDF]

				T. Saji, R. Kikuchi, H. Kusuhara, I. Kim, F. J. Gonzalez, and Y. Sugiyama Transcriptional Regulation of Human and Mouse Organic Anion Transporter 1 by Hepatocyte Nuclear Factor 1 {alpha}/{beta} J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 784 - 790. [Abstract] [Full Text] [PDF]