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.
Footnotes
-
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
-
doi:10.1124/mol.107.039701.
-
ABBREVIATIONS: OAT, organic anion transporter; URAT1, urate transporter 1; HNF1, hepatocyte nuclear factor 1; PCR, polymerase chain reaction; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; T-DMR, tissue-dependent differentially methylated region; MODY, maturity-onset diabetes of the young; HEK, human embryonic kidney; wt, wild-type hepatocyte nuclear factor 1 motif in the hURAT1 promoter; per, the consensus sequence for the hepatocyte nuclear factor 1 motif; mut, mutated hepatocyte nuclear factor 1 motif; m, mouse; h, human.
- Received July 6, 2007.
- Accepted September 10, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|