Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo 181-8611, Japan
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ABSTRACT |
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Recently, we isolated the multispecific organic anion
transporter (OAT1) from the rat kidney, which plays important roles in
the renal elimination of endogenous and exogenous organic anions including clinically important drugs. In the present study, we cloned
and characterized human OAT1. Two cDNA clones, hOAT1-1 cDNA and
hOAT1-2 cDNA, were isolated from a human kidney cDNA library,
whose amino acid sequences were 86.0% and 87.8% identical to that of
rat OAT1, respectively. When expressed in Xenopus
laevis oocytes, hOAT1 mediated sodium-independent
uptake of p-aminohippurate (PAH)
(Km = 9.3 ± 1.0 µM). hOAT1-mediated PAH uptake was inhibited by bulky
inorganic anions, various xenobiotics, and endogenous substances, including benzylpenicillin, furosemide, indomethacin, probenecid, phenol red, urate, and -ketoglutarate. Northern blot analysis revealed that hOAT1 mRNA is strongly expressed in human kidney; transcripts of different sizes are expressed in skeletal muscle, brain, and placenta. Immunohistochemical analysis using rabbit
IgG antibody against the carboxy-terminal 14 peptides of hOAT1 revealed
that hOAT1 is expressed at the basolateral membrane of the proximal
tubule. hOAT1 gene was located on
human chromosome 11q13.1 by fluorescent in situ hybridization analysis.
These results indicate that hOAT1 is a multispecific organic anion
transporter on the basolateral membrane of the proximal tubule in human kidney.
p-aminohippurate; immunohistochemical analysis; fluorescent in situ hybridization
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INTRODUCTION |
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EXCRETION OF ORGANIC ANIONS from the kidney has been used for the clinical evaluation of renal function. p-Aminohippurate (PAH) and phenolsulphonphthalein (PSP, phenol red) are substrates of the organic anion transport system in the proximal tubule. The secretion of PAH, in particular, is very efficient, and PAH has been used for the estimation of the renal plasma flow (2).
The transporter that mediates PAH transport across the basolateral
membrane of the proximal tubule in the kidney has been known as a
multispecific transporter. It has been presumed that this PAH
transporter takes up a variety of organic anions with different
chemical structures including not only endogenous organic anions but
also a number of clinically important anionic drugs, such as -lactam
antibiotics, diuretics, nonsteroidal anti-inflammatory drugs,
angiotensin converting enzyme inhibitors, and methotrexate (14, 23).
Because of this multispecificity, drug-drug interactions can occur when
several drugs that are substrates for this transporter are administered
concomitantly to a patient. Thus the characterization of human organic
anion transporter would be very important for understanding the
pharmacokinetics of anionic drugs and the mechanism of nephrotoxicity
of certain drugs in the human kidney.
Recently, we isolated a multispecific organic anion transporter 1 (OAT1) from rat kidney as a PAH transporter (20). Other than PAH, OAT1 transports a variety of organic anions as has been predicted (20). Independently, cDNAs encoding renal organic anion transporter from winter flounder (fROAT1) (25) and from rat (ROAT1) (22) were isolated. Amino acid sequence of ROAT1 is 100% identical to that of OAT1, whereas that of fROAT shows 46.9% identity to that of OAT1. At the present time, it is uncertain whether fROAT1 is in the same gene family as OAT1. NKT, which has been cloned from mouse kidney cDNA library (12), was found to have high identity of amino acid sequence to that of OAT1. Although the transport characteristics have not been demonstrated yet, NKT is considered to be the mouse homolog of OAT1.
In an attempt to understand the functional properties and substrate selectivity of the human organic anion transporter, we isolated and characterized the human OAT1 (hOAT1).
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METHODS |
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Screening of human kidney cDNA
library. A cDNA library, in the vector ZIPLOX (Life
Technologies, Gaithersburg, MD), was constructed from human kidney
poly(A)+ RNA (Clontech, Palo Alto,
CA) using the Superscript Choice System (Life Technologies). Copies
from the library were transferred onto nitrocellulose filters (Protran
BA45; Schleicher & Schuell, Keene, NH). The human kidney cDNA library
was screened with the full-length rat OAT1 cDNA. Hybridization was
performed at 45°C in 50% formamide, and washing was performed with
0.1× SSC buffer (1× SSC is 150 mM NaCl and 15 mM sodium
citrate, pH 7.0) and 0.1% SDS at 42°C. Plasmids were obtained by
in vivo excision, according to the instructions of the manufacturer.
Inserts were excised using EcoR I and
subcloned into the EcoR I site of
pBluescript II SK
(Stratagene, La Jolla, CA). All subsequent studies were performed using
the subcloned plasmids.
cDNA sequencing and analysis. For the sequencing of the hOAT1 clone, deleted clones of both strands were obtained using the KiloSequence deletion kit (Takara). These were electrophoresed and analyzed using the dye primer cycle sequencing kit (Perkin-Elmer) and the automated Applied Biosystems 310 DNA sequencer. Synthetic oligonucleotide primers and the dye terminator cycle sequencing kit were also used to complete the sequencing. The sequence was assembled and analyzed using DNASIS-Mac ver.3.6 (Hitachi Software Engineering).
Functional characterization of human OAT1. Xenopus laevis oocyte expression studies and uptake measurements were performed as described previously (10). Defolliculated oocytes were injected with in vitro-transcribed hOAT1 cRNA. In vitro transcription was performed using T7 RNA polymerase in the presence of the Cap analog. After incubation of oocytes at 18°C for 3-4 days and preincubation with glutarate, uptake studies were performed in a sodium uptake solution (100 mM NaCl, 2 mM KCl, 1 mM MgCl2 · 6H2O, 1 mM CaCl2 · 2H2O, 10 mM HEPES, and 5 mM Tris, pH 7.5) containing radiolabeled substrates.
Northern blot analysis. According to
the instructions of the manufacturer, human MTN Blot I (Clontech) was
hybridized at 68°C for 1 h in the ExpressHyb Hybridization Solution
(Clontech) with full-length hOAT1-1 cDNA or human -actin cDNA
labeled with
[32P]dCTP. The filter
was finally washed in 0.1× SSC + 0.1% SDS at 50°C.
Immunohistochemical analysis. For immunohistochemical analysis, rabbits were immunized with a keyhole limpet hemocyanin-conjugated synthesized peptide, CMVPLQASAQEKNGL, corresponding to cysteine and the 14 amino acids of the COOH terminus of hOAT1. The IgG fraction of the polyclonal antibodies for the synthesized peptide was purified from the serum of immunized rabbits using protein A column (Nihongaishi). Two-micrometer wax sections of nephrectomized human kidney were processed for light microscopic immunohistochemical analysis, using the streptavidin-biotin-horseradish peroxidase complex technique (LSAB kit; DAKO, Carpinteria, CA). The renal tissue was from a tumor patient and approved by the Kyorin University Institutional Research Board (IRB) to be used for medical study. Sections were dewaxed, rehydrated, and incubated with 3% H2O2 for 10 min to eliminate endogenous peroxidase activity. After rinsing in 0.05 M Tris-buffered saline containing 0.1% Tween-20, sections were treated with 10 µg/ml of the IgG fraction of primary rabbit polyclonal antibodies (room temperature, 2 h). Thereafter, the sections were incubated with the secondary antibody, biotinylated goat polyclonal antibody against rabbit immunoglobulin (DAKO), diluted 1:400 for 30 min. The sections were then rinsed and incubated for 30 min with horseradish peroxidase-labeled streptavidin. This step was followed by incubation with diaminobenzidine and hydrogen peroxide. The sections were counterstained with hematoxylin and examined by light microscopy.
Fluorescent in situ hybridization
analysis. Lymphocytes isolated from human blood were
cultured in -minimal essential medium (
-MEM) supplemented with
10% fetal calf serum and phytohemagglutinin at 37°C for 68-72
h. The lymphocyte cultures were treated with 0.18 mg/ml
bromodeoxyuridine (Sigma) to synchronize the cell population. The
synchronized cells were washed three times with serum-free medium to
release the block and recultured at 37°C for 6 h in
-MEM with
2.5 µg/ml thymidine (Sigma). Cells were harvested and slides were
made using standard procedures including hypotonic treatment, fixation,
and air drying. The hOAT1 probe was biotinylated with dATP using the
BRL BioNick labeling kit (15°C, 1 h) (6). The slides were then
baked at 55°C for 1 h. After the RNase treatment, the slides were
denatured in 70% formamide in 2× SSC for 2 min at 70°C
followed by dehydration with ethanol. Probes were denatured at 75°C
for 5 min in a hybridization mixture consisting of 50% formamide and
10% dextran sulfate. Probes were applied to the denatured chromosomal
slides. After overnight hybridization, the slides were washed and
screened, as well as amplified. The fluorescent in situ hybridization
(FISH) signals and 4,6-diamidino-2-phenylindole (DAPI) banding patterns
were recorded separately by taking photographs, and the assignment of
the FISH mapping data to chromosomal bands was achieved by
superimposing FISH signals with DAPI-banded chromosomes (7).
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RESULTS |
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Amino acid sequence of hOAT1. Using the rat OAT1 cDNA as a probe, four cDNAs were isolated from the human kidney cDNA library after two rounds of screening. Enzyme maps revealed that two kinds of cDNAs, designated as hOAT1-1 and hOAT1-2, were cloned. One clone is human hOAT1-1, and the other three clones were full or partial lengths of the hOAT1-2. hOAT1-1 cDNA and hOAT1-2 cDNA consisted of 2,171 bp and 2,134 bp, respectively. The ATG translation initiation codons of hOAT1-1 were assigned at nucleotide 268 by the comparison with the rat OAT1 sequence. hOAT1-1 cDNA contained a 1,689-bp open-reading frame that encoded a 563-amino acid protein with an estimated molecular mass of 61,813 Da. Nucleotides 1834-1872 of hOAT1-1 cDNA were absent in the nucleotide sequence of the hOAT1-2 cDNA, resulting in a 13-amino acid deletion (W523-R535) in hOAT1-2. Figure 1 compares the deduced amino acid sequences of hOAT1-1, rOAT1, NKT, and fROAT. The amino acid sequence of hOAT1-1 exhibited 86.0% and 82.9% identity to that of rOAT1 and NKT, respectively. The amino acid sequence of hOAT1-2 exhibited 87.8% and 84.8% identity to that of rOAT1 and NKT, respectively. The amino acid sequences of hOAT1-1 and 1-2 exhibited 46.8% and 47.4% identity to that of fROAT1, respectively.
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It was predicted that hOAT1 had 12 membrane-spanning domains, based on the Kyte-Doolittle hydropathy analysis. Five potential N-glycosylation sites (at amino acids 39, 56, 92, 97, and 113) were predicted in the first hydrophilic loop. There are four putative protein kinase C-dependent phosphorylation sites (at amino acids 271, 278, 284, and 526) in the hydrophilic loops (Fig. 2).
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Functional characterization of hOAT1. Figure 3A shows hOAT1-mediated [14C]PAH uptake in X. laevis oocytes. hOAT1-1 and hOAT1-2 have the same level of PAH transport activity. In the following experiments, hOAT1-1 cDNA was used for the functional characterization. As shown in Fig. 3B, hOAT1-mediated PAH uptake follows Michaelis-Menten kinetics, and the estimated Km value was 9.3 ± 1.0 µM (mean ± SE, n = 3).
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Figure 4 shows the attenuation of
hOAT1-mediated PAH uptake by the substitution of extracellular chloride
anion with other inorganic anions or mannitol. The replacement of
extracellular sodium with choline had no effect on the rate of
hOAT1-mediated PAH uptake. However, when extracellular
Cl was substituted with
other anions or mannitol, hOAT1-mediated PAH uptake was depressed.
Thiocyanate anion partially decreased the uptake, but sulfate anion,
gluconate anion, and mannitol strongly depressed hOAT1-mediated PAH
uptake.
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To evaluate the substrate selectivity of hOAT1, we examined the
inhibitory effects of various organic anions on hOAT1-mediated [14C]PAH uptake (Fig.
5).
cis-Inhibitory effects were observed
with furosemide (a loop diuretic), indomethacin (a nonsteroidal
anti-inflammatory drug), probenecid (a uricosuric drug), and phenol red
(PSP, a diagnostic reagent). Benzylpenicillin potassium (PCG-K, an
antibiotic) also inhibited hOAT1-mediated PAH uptake. Other endogenous
compounds, such as urate and -ketoglutarate, also inhibited
hOAT1-mediated PAH uptake.
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Northern blot analysis of hOAT1. In highly stringent Northern blot analysis, 2.1-kb and 6.5-kb mRNA was detected by the full-length hOAT1-1 cDNA probe in the human kidney; mRNAs at ~3.8 and 4.4 kb were also detected in the kidney using the same probe but at a much lower intensity. A 1.3-kb mRNA was detected in skeletal muscle, and faint mRNA bands were detected in the brain (4.8 kb) and placenta (4.2 kb). There were no positive signals in the heart, lung, liver, or pancreas (Fig. 6).
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hOAT1 expression in human kidney. Figure 7 shows immunohistochemical analysis of hOAT1 in human kidney. The IgG fraction of rabbit polyclonal antibodies against the 14 amino acids of the carboxy terminus of hOAT1 strongly stained the proximal tubule cells. No staining was observed in arteries, glomeruli, the thick portion of the ascending loop of Henle, distal tubule, and collecting duct cells. In proximal tubule cells, hOAT1 was localized exclusively at the basolateral membrane.
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FISH mapping. Under the conditions described in METHODS, the hybridization efficiency was ~83% for this probe. Since DAPI banding was used to identify the specific chromosome, the signal from the probe could be assigned to the long arm of chromosome 11 (Fig. 8, A and B). The detailed position was further determined based on the summary of the 10 photos (Fig. 8C). No additional loci were determined by the FISH mapping under these conditions. Therefore, it was concluded that the hOAT1 gene is located on human chromosome 11, region q13.1.
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DISCUSSION |
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Using the full length of rat OAT1 cDNA, we isolated two types of cDNA clones from a human kidney cDNA library and designated these as hOAT1-1 and hOAT1-2. Since the mRNA of hOAT1-1 was detected by RT-PCR of human kidney poly(A)+ RNA using the unique sequence of hOAT1-1 cDNA as a primer, hOAT1-1 cDNA is not an artifact of cDNA library construction, but is really transcribed in human kidneys (data not shown). FISH studies revealed that the hOAT1 gene is located at the only locus of the human chromosome 11. Thus the mRNA of hOAT1-2 is probably a differently spliced mRNA of hOAT1-1, possibly a result of the alternative-splicing mechanism.
The structure and the functional characteristics of hOAT1-1, affinity for PAH, and substrate selectivity were similar to those of rat OAT1, indicating that hOAT1 could be the organic anion/dicarboxylate exchanger in human kidney. Immunohistochemical analysis revealed that hOAT1 is expressed at the basolateral membrane of the proximal tubule cells of human kidney. Thus hOAT1, as a multispecific organic anion transporter, mediates active transport of organic anions from the interstitium to the cell against electrochemical potential gradient at the basolateral membrane of proximal tubule in human kidney.
Compounds shown in Fig. 5, which inhibited PAH uptake via hOAT1, are candidates for transport substrates of hOAT1. Since these xenobiotics bind to plasma protein extensively, they are minimally excreted by glomerular filtration. Previous pharmacokinetic studies on human body revealed that benzylpenicillin, furosemide, and PSP are excreted into urine unchanged, and hOAT1 probably transports these compounds into the proximal tubule cells in human kidney. Since furosemide, a loop diuretic, is also secreted by the proximal tubule and acts on the luminal side of the loop segment, the diuretic effect of loop diuretics relates to the tubular secretion via hOAT1. It may be an example of drug competition for hOAT1 that the diuretic effect of furosemide is attenuated by coadministration of probenecid (17). Probenecid also inhibits the excretion of benzylpenicillin and lengthens the half-life of benzylpenicillin concentration in serum (15). Thus the clarification of the substrate selectivity of hOAT1 contributes to the understanding of the pharmacokinetics of anionic drugs and their interactions in the renal excretion.
The original role of hOAT1 is presumed to be the mediation of transport of endogenous anionic compounds such as cyclic nucleotides (4, 16), prostaglandins (9), and uremic toxins (18). Urate has posed a special problem in humans, because it has limited solubility in physiological solutions and humans possess no uricase, the enzyme that oxidizes urate to the more soluble compound, allantoin. Urate and PAH may be secreted by the same carrier in rabbits, pigs, and guinea pigs, which do not reabsorb urate in the kidney (11). In contrast, excretion of urate in humans was reported to be unaffected by the administration of PAH. Therefore, separate carriers appear to exist in humans (1). Further study is required for the elucidation of the role of hOAT1 in urate transport in the human kidney.
It has been reported that the substitution of extracellular
Cl with other anions or
mannitol decreased the uptake of PAH by sliced rabbit kidney (5),
basolateral membrane vesicles from rat kidneys (8), and basolateral
membrane vesicles from bovine kidney (19). As shown in Fig. 4, the
replacement of Cl
with
other anions suppressed hOAT1-mediated PAH uptake. Although the effects
of the substitution of inorganic anions for
Cl
on the
sodium-dicarboxylate cotransporter was not disputed, it was clear that
inorganic anions affected the PAH transporter, hOAT1.
As in the case of the kidney, anionic substrates are also transported in other organs, e.g., choroid plexus (13), eye (21), airway (3), and placenta (24). In highly stringent Northern blot analysis, faint signals were detected in brain and placenta samples; hOAT1 may mediate the transport of organic anions in these tissues. A cDNA clone in the EST database, clone ID-36482, which was derived from the infant brain cDNA library, has a nucleotide sequence identical to a partial sequence of hOAT1-2. The identification of isoforms of hOAT1 in other organs would facilitate understanding of drug delivery and their excretion from the body and would prove useful for developing drugs that would facilitate a desirable distribution pattern in the body.
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ACKNOWLEDGEMENTS |
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We thank Dr. Nobuaki Watanabe and Sankyo Pharmaceutical for nucleotide sequencing using the automated Applied Biosystems 310 DNA sequencer and the dye primer cycle sequencing kit and for synthesizing the peptide corresponding to the COOH terminus of hOAT1. We thank Panapharm for production of the IgG fraction of anti-hOAT1 antibody. We also thank Dr. H. Heng and SeeDNA Biotech for help with the FISH experiment.
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FOOTNOTES |
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This study was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan (09470025, 09257241), by the Science Research Promotion Fund from Japan Private School Promotion Foundation, and by the Fugaku Trust for Medicinal Research.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: H. Endou, Dept. of Pharmacology and Toxicology, Kyorin Univ. School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan.
Received 23 April 1998; accepted in final form 28 September 1998.
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