Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 α/β and DNA methylation

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

Research output: Contribution to journalArticle

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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. To elucidate the mechanism underlying its tissue-specific expression, the transcriptional regulation of the hURAT1 and mUrat1 genes was investigated. Hepatocyte nuclear factor 1 α (HNF1α) and HNF1β positively regulate minimal promoter activity of the URAT1 gene as shown by reporter gene assays. Electrophoretic mobility shift assays revealed binding of HNF1α and/or HNF1β to the HNF1 motif in the hURAT1 promoter. Furthermore, the mRNA expression of Urat1 is reduced in the kidneys of Hnf1α-null mice compared with wild-type mice, confirming the indispensable role of HNF1α 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 HNF1α/HNF1β heterodimer and repression by DNA methylation.

Original languageEnglish
Pages (from-to)1619-1625
Number of pages7
JournalMolecular Pharmacology
Volume72
Issue number6
DOIs
Publication statusPublished - 2007 Dec
Externally publishedYes

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Hepatocyte Nuclear Factor 1
DNA Methylation
Genes
Kidney Cortex
Kidney Medulla
Gene Expression
Proximal Kidney Tubule
Mouse Slc22a12 protein
Electrophoretic Mobility Shift Assay
Uric Acid
Reporter Genes
Genetic Promoter Regions
Methylation
Transcriptional Activation
Kidney

ASJC Scopus subject areas

  • Pharmacology

Cite this

Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 α/β and DNA methylation. / Kikuchi, Ryota; Kusuhara, Hiroyuki; Hattori, Naka; Kim, Insook; Shiota, Kunio; Gonzalez, Frank J.; Sugiyama, Yuichi.

In: Molecular Pharmacology, Vol. 72, No. 6, 12.2007, p. 1619-1625.

Research output: Contribution to journalArticle

Kikuchi, Ryota ; Kusuhara, Hiroyuki ; Hattori, Naka ; Kim, Insook ; Shiota, Kunio ; Gonzalez, Frank J. ; Sugiyama, Yuichi. / Regulation of tissue-specific expression of the human and mouse urate transporter 1 gene by hepatocyte nuclear factor 1 α/β and DNA methylation. In: Molecular Pharmacology. 2007 ; Vol. 72, No. 6. pp. 1619-1625.
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