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

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 tubulerestricted 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. Urate is an end product of purine metabolism in humans and other higher primates. It is generally recognized that urate works as a scavenger of potentially harmful radicals in the human body. However, hyperuricemia can be associated with health problems such as gout, nephrolithiasis, hypertension, and vascular disease, whereas hypouricemia is primarily characterized by exercise-induced acute renal failure. Thus, the serum urate level must be tightly regulated through complex renal handling processes, which is historically explained by a four-component model (i.e., glomerular filtration, tubular secretion, and preand postsecretory reabsorption). After these processes, approximately 90% of the urate filtered through the glomerulus is reabsorbed in humans (Rafey et al., 2003; Enomoto and Endou, 2005; Hediger