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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Transcriptional Regulation of Human and Mouse Organic Anion Transporter 1 by Hepatocyte Nuclear Factor 1 /β

Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan (T.S., R.K., H.K., Y.S.); and Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (I.K., F.J.G.)

Received July 6, 2007; accepted November 19, 2007.

	Abstract

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Organic anion transporter 1 (OAT1/SLC22A6) is predominantly expressed in the proximal tubules of the kidney. Cumulative studies have shown its critical role in the tubular secretion of a variety of organic anions, including several clinically important drugs. In addition, OAT1 is also involved in the pharmacological effect of diuretics and the nephrotoxicity of antiviral drugs. In contrast to these functional characterizations, the regulatory mechanism of OAT1 expression is poorly understood. It was recently demonstrated that the expression of Oat1 was markedly reduced in the kidneys of hepatocyte nuclear factor 1 (Hnf1)-null mice. However, in vitro evidence for the involvement of HNF1 and further analyses are required to illustrate the transcriptional regulation of OAT1 genes in more detail. Computational analysis of the potential transcription factor binding sites revealed that the HNF1-motif was conserved in the proximal-promoter region of human and mouse OAT1 genes. The mRNA expression of mouse organic anion transporter 1 was drastically reduced in Hnf1-null mice compared with that in wild-type mice, which was consistent with a previous report (Maher et al., 2006). Forced expression of HNF1 alone or both HNF1 and HNF1β enhanced the activity of human and mouse OAT1 promoters in the transactivation assays, whereas HNF1β alone was not active. Mutations in the HNF1-motif significantly reduced this transactivation. Direct binding of HNF1/HNF1 homodimer and HNF1/HNF1β heterodimer to the HNF1-motif found in the human OAT1 promoter was demonstrated by electrophoretic mobility shift assays. These results provide convincing evidence for the involvement of HNF1/β in the constitutive expression of human and mouse OAT1 in the kidney.

We have recently characterized the transcriptional regulation of OAT3 and urate transporter 1 (URAT1/SLC22A12) and shown that the coordinated action of hepatocyte nuclear factor 1 /β (HNF1/β) and DNA methylation determines the kidney-specific expression of these transporters (Kikuchi et al., 2006, 2007). HNF1 consists of two isoforms, HNF1 and HNF1β, and activates the transcription of target genes via direct binding to their promoters after forming homodimers or heterodimers between the two isoforms (Mendel and Crabtree, 1991; Tronche and Yaniv, 1992). These transcription factors were originally identified to be involved in the maintenance of hepatic gene expression, such as albumin, 1-antitrypsin, and - and β-fibrinogen, as well as some of the organic anion transporters in the liver (Shih et al., 2001). As a result, cumulative reports including the analyses of gene-disrupted animals suggest the importance of HNF1/β in extrahepatic organs, such as the pancreas and kidney (Pontoglio et al., 1996; Lee et al., 1998; Gresh et al., 2004).

In the kidney, HNF1 exhibits restricted distribution within the proximal tubules, whereas HNF1β is expressed along the entire nephrons (Lazzaro et al., 1992; Pontoglio et al., 1996). HNF1 normally exists as the HNF1/HNF1β heterodimer or HNF1β/HNF1β homodimer in the proximal tubules, whereas HNF1β/HNF1β homodimer is predominantly expressed in the other segments. As for renal organic anion transporters, mRNA expression of Oat1, as well as Oat2 and Oat3 in the kidney, is reduced in Hnf1-null mice, suggesting the role of HNF1 in the transcription of organic anion transporters not only in the liver but also in the kidney (Maher et al., 2006). Computational analysis of the human and mouse OAT1 5'-flanking sequences revealed that the HNF1-motif is conserved in the proximal-promoter region of OAT1 genes (Fig. 1). On the other hand, Ogasawara et al. (2007) recently reported that HNF4, an orphan member of the nuclear receptor superfamily, enhances the promoter activity of human OAT1, whereas the effect of HNF1 or HNF1β was minimal. HNF4 forms homodimers to bind to a DNA sequence corresponding to a direct repeat of AGGTCA-like hexamers separated by one or two nucleotides (DR1 or DR2, respectively) or an inverted repeat of the hexamers separated by eight nucleotides (IR-8) (Sladek et al., 1990; Fraser et al., 1998; Prieur et al., 2005) and regulates the hepatic expression of human organic anion transporter 2 (SLC22A7) and organic cation transporter 1 (SLC22A1) under both physiological and pathological conditions (Popowski et al., 2005; Saborowski et al., 2006). Although HNF4 is found in the proximal tubules in the kidney (Jiang et al., 2003), the physiological significance of HNF4 in the kidney is poorly recognized due to the embryonic death of Hnf4-null mice (Chen et al., 1994). Furthermore, it has yet to be investigated whether HNF1/β is actually involved in the transcription of the human OAT1 gene, as is the case with OAT3 and URAT1.

View larger version (31K): [in this window] [in a new window]   Fig. 1. Alignment of the proximal promoters of human and mouse OAT1 genes. Nucleotide sequences of human and mouse OAT1 promoter regions were aligned using Genetyx-win version 8 software to illustrate the high homology of the 5'-flanking sequences between species. Nucleotide numberings are relative to the transcriptional start sites indicated by an arrow (+1), and homologous sequences between species are boxed. The putative HNF1-motif and the IR-8 element are shaded, and CpG dinucleotides in each sequence are reverse-colored.

	Materials and Methods

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Materials. All reagents were purchased from Wako Pure Chemicals (Osaka, Japan) unless stated otherwise.

Preparation of Total RNA and Quantitative Polymerase Chain Reaction. Total RNA was isolated from the kidney of 7 to 14-week-old male (n = 3) and female (n = 4) wild-type or Hnf1-null mice (Lee et al., 1998), and it was treated with DNase I to eliminate the contaminated genomic DNA. The total RNA was reverse-transcribed using a random-nonamer primer (Takara, Shiga, Japan), and real-time quantitative polymerase chain reaction (PCR) was performed as previously described (Kikuchi et al., 2006) using the primers shown in Table 1 to quantify the mRNA expression of mouse organic anion transporter 1 (mOat1). The mRNA expression of mOat1 was normalized by the mRNA expression of GAPDH and statistically analyzed by the Student's t test.

Isolation of the 5'-Flanking Region of the hOAT1 and mOat1 Genes. The transcriptional start site of the hOAT1 and mOat1 gene was identified based on the information in the public database, Database of Transcriptional Start Sites (http://dbtss.hgc.jp/), with the reference sequence identification for hOAT1 and mOat1 (NM_004790 and NM_008766, respectively). The position of the potential transcription factor binding sites in human and mouse OAT1 promoter regions was determined using MatInspector (http://www.genomatix.de/) or NUBIScan (http://pages.unibas.ch/wtt/Products/Nubiscan/nubiscan.html) (Podvinec et al., 2002). The 919- and 110-base pair (bp) 5'-flanking regions of the human and mouse OAT1 gene were amplified by PCR using human and mouse genomic DNA as a template, respectively. An artificial KpnI or HindIII restriction site was added to the primer sequences, which are shown in Table 1. The PCR products were digested with KpnI and HindIII after subcloning into pGEM-T Easy vector (Promega, Madison, WI) and ligated into pGL3-Basic vector (Promega) predigested with KpnI and HindIII, yielding the hOAT1_-919/+11_HNF1wt and mOat1_-110/+10_HNF1wt promoter-reporter construct. A series of hOAT1 5'-truncated promoter fragments (-623/+11, -318/+11, and -111/+11) were PCR-amplified using hOAT1_-919/+11_HNF1wt plasmid as a template (the primers are shown in Table 1) and then inserted into the pGL3-Basic vector as described above, yielding the following promoter constructs: hOAT1_-623/+11_HNF1wt, -318/+11_HNF1wt, and -111/+11_HNF1wt. The sequence identity of all the constructs with the respective genomic sequences was verified by DNA sequencing. Plasmid DNA was prepared using the GenElute Plasmid Midiprep kit (Sigma-Aldrich, St. Louis, MO).

Site-Directed Mutagenesis. All of the mutated promoter fragments (HNF1mut) having a 4-bp-disrupted HNF1-motif were generated with a QuikChange XL Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA) using internally mutated oligonucleotides with sense sequence (as shown in Table 1) according to the manufacturer's instructions. The introduction of mutations was verified by DNA sequencing. The positions and bases that will replace the original sequences were decided based on the information in the database of transcription factors TRANSFAC (http://www.gene-regulation.com/); highly conserved bases in the consensus HNF1-motif were mutated into bases with the lowest frequency at the corresponding position.

Cell Culture, Transfections, and Luciferase Assays. Cell culture and transfections were performed as described previously. In transactivation assays, 0.5 µg of empty pcDNA3.1⁺ control vector, 0.5 µg of HNF1 expression vector, 0.25 µg of HNF1 and HNF1β expression vectors, or 0.5 µg of HNF1β expression vector was cotransfected with 0.5 µg of the corresponding promoter construct and 0.05 µg of internal standard pRL-SV40 into HEK293 cells. The promoter activity was measured as relative light units of firefly luciferase per unit of Renilla luciferase. The difference in the promoter activity between wild-type and HNF1-mutated reporter constructs was statistically analyzed by the Student's t test.

In Vitro Translation. In vitro translation was performed using TNT Quick Coupled Transcription/Translation kits (Promega) according to the manufacturer's instructions. One microgram of empty pcDNA3.1⁺ control vector, 1 µg of HNF1 expression vector, 0.5 µgof HNF1 and HNF1β expression vectors, or 1 µg of HNF1β expression vector was added to the TNT Quick master mix. The mixture was then incubated at 30°C for 75 min and used for additional analyses. The HNF1 and HNF1β proteins were prepared at least twice, and the reproducible binding to the labeled OAT1 probe was confirmed.

Electrophoretic Mobility Shift Assay. Double-stranded oligonucleotide probes were generated by hybridizing single-stranded complementary oligonucleotides with sense sequences (shown in Table 1). The sequence "wt" corresponds to the wild-type HNF1-motif found in the hOAT1 promoter, and "per" corresponds to the perfect consensus sequence for the HNF1-motif, whereas "mut" denotes the wild-type sequence mutated in the motif. Electrophoretic mobility shift assay (EMSA) was performed as previously described with Dig Gel Shift Kit, 2nd Generation (Roche Diagnostics, Indianapolis, IN) (Kikuchi et al., 2006). In brief, 2.5 µl of in vitro-translated HNF1 and/or HNF1β was incubated on ice for 30 min in the binding solution containing 0.92 pmol of digoxigenin-labeled probe. A 100-fold excess of unlabeled oligonucleotides and 1 µg of antibody against HNF1 or HNF1β (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) were added to the reaction for competition and supershift assays, respectively. The experiments were independently performed three times, and the representative images are shown.

	Results

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Computational Analysis of the Potential Transcription Factor Binding Sites in Human and Mouse OAT1 Promoters. The promoter sequences of the human and mouse OAT1 genes were obtained from the National Center for Biotechnology Information genome database and aligned using Genetyx-win version 8 software (Fig. 1). The promoter region of OAT1 was highly conserved between human and mouse, especially up to approximately 100 bp upstream of the transcriptional start site. Computational analysis using MatInspector revealed that the HNF1-motif is conserved at -56 to -44 relative to the transcriptional start site in both promoters, indicating the functional importance of this motif. Analysis using NUBIScan demonstrated that the IR-8 element was located at -123 to -104 in the hOAT1 promoter, but not in the mOat1 promoter, suggesting the possible existence of a species difference in the regulation of OAT1 expression.

Impaired Expression of mOat1 in the Kidney of Hnf1-Null Mice. The mRNA expression of mOat1 in male and female Hnf1-null mice was measured by real-time quantitative PCR (Fig. 2). The expression of mOat1 mRNA was approximately 3-fold higher in male kidney than in female in wild-type controls, which is consistent with the previous findings (Buist and Klaassen, 2004). Inactivation of HNF1 led to a significant reduction in the expression of mOat1 in male mice. In females, the expression of mOat1 mRNA was reduced by two-thirds in Hnf1-null mice compared with wild-type mice. These results clearly document the importance of HNF1 in the transcriptional regulation of the mOat1 gene in the kidney.

View larger version (13K): [in this window] [in a new window]   Fig. 2. Relative mRNA expression of mOat1 in wild-type and Hnf1-null mice. mRNA expression of mOat1 in the kidneys of male or female wild-type (WT, ) and Hnf1-null mice (null, ) was quantified as described under Materials and Methods. The data were normalized by the mRNA expression of GAPDH. The relative mRNA expression was given as a ratio with respect to the mRNA expression of mOat1 in male wild-type mice that was taken as 100%. Results are presented as the mean ± S.E. of three (male) or four (female) mice. ***, P < 0.001, significantly different between the indicated data points.

Transactivation of the Human and Mouse OAT1 Promoter by HNF1/

View larger version (26K): [in this window] [in a new window]   Fig. 3. Transactivation of human and mouse OAT1 promoters by HNF1 and/or HNF1β. A, HEK293 cells were transfected with mOat1 wild-type promoter (mOat1_-110/+10_HNF1wt), or a promoterless pGL3-Basic plasmid, together with empty pcDNA3.1+ vector (white bars), HNF1 expression vector (black bars), HNF1, and HNF1β expression vectors (gray bars), or HNF1β expression vector (hatched bars). The luciferase activity was measured as described under Materials and Methods and was shown as the factor of induction over background activity measured in cells transfected with pGL3-Basic together with pcDNA3.1+. B, the activity of a series of hOAT1 wild-type or HNF1-mutated promoters in the presence or absence of exogenously expressed HNF1 and/or HNF1β was measured as described in A. Results are presented as the mean ± S.E. of triplicate samples. *, P < 0.05, **, P < 0.01, and ***, P < 0.001, significantly different between wild-type and the corresponding HNF1-mutated promoters.

Direct Binding of HNF1/β to the hOAT1 Promoter. To confirm the direct binding of HNF1/β to the hOAT1 promoter, EMSA was performed with the oligonucleotide probe corresponding to the HNF1-motif found in the hOAT1 promoter and in vitro-translated HNF1 and/or HNF1β (Fig. 4A). The expression of in vitro-translated HNF1 or HNF1β was confirmed by Western blot analysis with specific antibodies against HNF1 or HNF1β, respectively (data not shown). When the probe was incubated with HNF1 alone or both HNF1 and HNF1β, one- (Fig. 4A, band a, lane 3) or two-shifted bands (Fig. 4A, bands a and b, lane 7) were observed, respectively, whereas there was no shifted band when the probe was incubated with HNF1β alone (lane 11). In all samples using the in vitro-translated products, a broad signal was detected below the bands (Fig. 4A, bands a and b). It is likely that this signal represents nonspecific binding to the labeled probe because the signal was also detected when in vitro-translated empty pcDNA3.1⁺ was incubated with the probe (Fig. 4A, lane 2). Formation of both bands a and b (Fig. 4A) was completely abolished by adding a 100-fold excess of the unlabeled competitor corresponding to the consensus sequence for the HNF1-motif (Fig. 4A, lanes 4 and 8) and partly inhibited by the competitor corresponding to the hOAT1 wild-type promoter sequence (Fig. 4A, lanes 5 and 9). On the other hand, these bands were not affected by the addition of the mutated competitor (Fig. 4A, lanes 6 and 10). These results suggest that bands a and b (Fig. 4A) can be ascribed to the binding of HNF1 or HNF1β to the HNF1-motif in the hOAT1 promoter.

View larger version (20K): [in this window] [in a new window]   Fig. 4. Direct binding of HNF1 and HNF1β to the hOAT1 promoter. A, competition assays are shown. A digoxigenin-labeled probe corresponding to the hOAT1 wild-type promoter containing the HNF1-motif was incubated with in vitro-translated HNF1 and/or HNF1β, or pcDNA3.1+ as a negative control, in the presence or absence of a 100-fold excess of unlabeled competitor (per, wt, or mut) as indicated. B, supershift analysis is shown. The probe was incubated with HNF1 alone or both HNF1 and HNF1β in the presence or absence of a specific antibody against HNF1 () or HNF1β (β) as indicated. The DNA-protein complex was detected as described under Materials and Methods. The representative images of three independent experiments are shown.

	Discussion

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Cumulative evidence suggests that HNF1 and/or HNF1β play a critical role in the expression of drug transporters in the liver and kidney. Several groups, including us, have shown that the HNF1-motif located within approximately 100 bp of the 5'-flanking region is involved in the transcriptional regulation of these transporters, i.e., -65 to -53 in the OAT3 promoters, -70 to -58 in the URAT1 promoters, -51 to -39 in the organic anion-transporting polypeptide 1B1 promoter, and -60 to -48 in the organic anion-transporting polypeptide 1B3 promoter (Jung et al., 2001; Kikuchi et al., 2006, 2007). Consistent with this finding, a database search for the potential transcription factor binding sites revealed that an HNF1-motif is conserved from -56 to -44 relative to the transcriptional start sites of the human and mouse OAT1 promoters (Fig. 1). These observations as well as the reduced expression of mOat1 in the kidney of Hnf1-null male mice (Maher et al., 2006) prompted us to investigate the role of HNF1/β in the transcriptional regulation of human and mouse OAT1 genes.

The involvement of HNF1 and/or HNF1β in the transcriptional regulation of human and mouse OAT1 genes was revealed by in vivo (Fig. 2) and in vitro experiments (Figs. 3 and 4). It is generally accepted that the transactivation potency of HNF1β is lower than that of HNF1 (Rey-Campos et al., 1991). Indeed, exogenous expression of HNF1β alone enhanced the promoter activity of OAT3 and URAT1 by at most 50% compared with that of HNF1 alone (Kikuchi et al., 2006, 2007). In the present study, HNF1β alone hardly stimulated the promoter activity of the human and mouse OAT1 genes, and no direct binding of HNF1β/HNF1β homodimer to the hOAT1 promoter could be detected. HNF1β exhibited less activity against the OAT1 promoters than OAT3 and URAT1 promoters. Therefore, it is likely that the contribution of HNF1β/HNF1β homodimer to the expression of OAT1 is much smaller than that of OAT3 and URAT1.

Ogasawara et al. (2007) demonstrated that HNF4 markedly transactivated the hOAT1 promoter through direct binding to the IR-8 element, whereas neither HNF1 nor HNF1β affected the promoter activity. On the other hand, we have provided clear evidence for an essential role of HNF1 in human and mouse OAT1 expression. We also confirmed that HNF4 transactivates the hOAT1 promoter. Cotransfection of HNF4 into HEK293 cells enhanced the promoter activity of the hOAT1_-919/+11_HNF1wt construct 3-fold compared with the pcDNA3.1⁺-transfected control (data not shown). Therefore, the experimental conditions may not be appropriate for examining the effect of HNF1/β in the previous report. The two studies used different cell lines as host. We used HEK293 cells that lack the endogenous expression of HNF1/β, whereas Ogasawara et al. (2007) used OK cells in which the endogenous expression of HNF1/β has not been investigated. The following difference in the reporter construct used could be another reason: hOAT1_-2747/+88 (Ogasawara et al., 2007) versus hOAT1_-919, -623, -318, or -111/+11_HNF1wt (present study).

In the kidney, the expression of both HNF1 and HNF4 is restricted to the proximal tubules (Lazzaro et al., 1992; Pontoglio et al., 1996; Jiang et al., 2003), consistent with the regional distribution of hOAT1 (Hosoyamada et al., 1999). Thus, the proximal tubule-specific expression of hOAT1 in the kidney is, at least partly, explained by the concerted effect of HNF1/HNF1β heterodimer and HNF4/HNF4 homodimer. However, the tissue distribution of HNF1β and HNF4 is much wider than that of OAT1 (Sladek et al., 1990; Blumenfeld et al., 1991; Rey-Campos et al., 1991; Miquerol et al., 1994; Drewes et al., 1996). Although OAT1 is exclusively expressed in the kidney, HNF1, HNF1β, and HNF4 are expressed in extrarenal tissues, such as the liver, intestine, and pancreas. We have recently shown that the kidney-specific expression of OAT3 and URAT1 genes is regulated by the synergistic effect of transcriptional activation by HNF1/β and repression by DNA methylation in the promoter region. However, unlike the minimal promoter regions of hOAT3 and human/mouse URAT1, there are few CpG dinucleotides in the human and mouse OAT1 promoter regions up to -400 bp (Fig. 1). It is noteworthy that OAT1 and OAT3 genes occur as a tightly linked pair on the same chromosome in the human and mouse genome with intergenic distances of 8.3 kilobase pairs in humans and 7.5 kilobase pairs in mice (Eraly et al., 2003). Both genes are transcribed to the same direction with OAT3 upstream of OAT1. The clustering of OAT1 and OAT3 in the genome raises the possibility that the methylation status of the OAT3 promoter region may affect the widespread chromatin configuration including the OAT1 gene, enabling DNA methylation-dependent gene silencing of OAT1 in extrarenal tissues. Future studies are required to show the in vivo relevance of the epigenetic regulation for OAT1 expression.

In conclusion, the present study clearly demonstrates that HNF1/HNF1β heterodimer plays a key role in the constitutive expression of human and mouse OAT1 genes. The transcriptional activation by HNF1 is a common feature among renal organic anion transporters, further emphasizing the role of this transcription factor in the regulation of endobiotics/xenobiotics transport in the kidney.

	Footnotes

 
T.S. and R.K. contributed equally to this work.

Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

doi:10.1124/jpet.107.128249.

ABBREVIATIONS: OAT, organic anion transporter; URAT, urate transporter; HNF, hepatocyte nuclear factor; hOAT, human OAT; PCR, polymerase chain reaction; mOat, mouse organic anion transporter; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; bp, base pair; HEK, human embryonic kidney; wt, wild type; mut, mutated wild-type sequence; EMSA, electrophoretic mobility shift assay.

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. E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

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