US20040265819A1 - Kidney-specific urate transporter and gene thereof - Google Patents

Kidney-specific urate transporter and gene thereof Download PDF

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US20040265819A1
US20040265819A1 US10/485,236 US48523604A US2004265819A1 US 20040265819 A1 US20040265819 A1 US 20040265819A1 US 48523604 A US48523604 A US 48523604A US 2004265819 A1 US2004265819 A1 US 2004265819A1
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uric acid
protein
leu
ala
analogs
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Hitoshi Endou
Yoshikatsu Kanai
Atsushi Enomoto
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Human Cell Systems Inc
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Human Cell Systems Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • the present invention relates to a gene participating in transport of uric acid and analogs thereof or exchange transport of uric acid and the other anion, and a polypeptide encoded by the gene.
  • uric acid which is an organic acid is a final metabolite in purine metabolism in cells, and is excreted mainly from the kidney.
  • species other than the human race and the primates it is metabolized to allantoin by an action of uricase in liver, and is excreted from the kidney. Therefore, for the other mammals, it seems that effects of dynamic abnormality of uric acid which is an intermediate product in the kidney on living body are small. Losing the action of uricase in the evolution process seems to be a cause of the fact that the human race has suffered from gout due to hyperuricemia since ancient times.
  • uric acid kinetics in the kidney has been studied by experimental systems using a removed organ perfusion method and an isolated cell membrane vesicle system. In humans, it has been demonstrated that uric acid freely passes through renal glomerulus and thereafter mechanisms for reabsorption and secretion exist in proximal convoluted tubule.
  • urate transport system via cell membrane is analyzed in detail, and it has been desired that the transporter per se is isolated and analyzed.
  • An object of the present invention is to identify and provide a novel urate transporter gene participating in the urate transport in the kidney and a urate transporter which is a polypeptide encoded by the above gene.
  • FIG. 1 shows the results of analyzing the expression of URAT1 gene messenger RNA in various organ tissues of human adult and embryo by Northern blotting.
  • FIG. 2 shows the result of time dependency in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 3 shows the result of concentration dependency in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 4 shows the result of examining the effects of added salts in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 5 shows the result of pH dependency in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 6 shows the result of preincubation with various organic acids in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 7 shows the result of examining the effect of previously injected unlabeled lactic acid (100 mM, 10 nl) in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 8 shows the result of examining the effects of addition of various organic acids or analog compounds thereof to the system in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 9 shows the result of examining the effects of probenecid addition at various concentrations to the system in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 10 shows the result of examining the effects of losartan addition at various concentrations to the system in uric acid uptake experiments by oocytes injected with cRNA of URAT1 gene.
  • FIG. 11 shows exon-intron structure of URAT1 gene in human genome.
  • the present inventors isolated four organic anion transporters, OTA1, OTA2, OTA3 and OTA4. They have about 40% homology of amino acid sequences each other. On the basis of these sequences, disclosed information of human genome project was searched, and multiple novel gene fragments having homology to OAT1, 2, 3 and 4 were identified. Among them, one novel gene fragment extremely closed to a gene locus position of OAT4 was analyzed, and a site supposed to be an initiation codon was identified. A primer specific for 5′ upstream of this initiation codon was made, and isolation of this novel gene was attempted by 3′-RACE (3-rapid amplification of cDNA ends) method using messenger RNA derived from various tissues of humans. As a result, a novel clone (URAT1) which had been never reported was identified by the 3′-RACE method using human kidney messenger RNA.
  • URAT1 novel clone
  • the urate transporter1, URAT1 of the present invention has an ability to transport uric acid and its analogs via cell membrane from one side to the other side and further is a urate/anion exchanger by making the anion at the other side of the cell membrane an exchange substrate.
  • the protein of the present invention includes, for example, those having the amino acid sequence in which one or several amino acids are deleted, substituted or added in the amino acid sequence represented by SEQ ID NO:1, in addition to one having the amino acid sequence represented by SEQ ID NO:1.
  • the amino acids could be deleted, substituted or added to the extent where urate transport activity is not lost, and typically from 1 to about 110 and preferably from 1 to about 55.
  • Such proteins typically have up to 75% and preferably up to 90% homologous amino acid sequences to the amino acid sequence represented by SEQ ID NO:1.
  • the isolation of the gene by the 3′-RACE method can be carried out typically by making a primer of about 30 bases specific for guanine- or cytosine-rich gene at the 5′ upstream of the initiation codon, performing reverse transcription of tissue-derived messenger RNA using an oligo dT primer with an adapter sequence, and subsequently performing PCR (polymerase chain reaction) using the adapter sequence and the gene-specific primer. It is possible to further enhance accuracy of the PCR by the use of heat resistant polymerase with higher fidelity.
  • the urate transporter gene of the present invention can be isolated and yielded by screening cDNA library prepared using renal tissues or cells in an appropriate mammal as a gene source.
  • the mammals include human in addition to non-human animals such as dog, cattle, horse, goat, sheep, monkey, swine, rabbit, rat and mouse.
  • the screening and isolation of the gene can be suitably carried out by homology screening and PCR method.
  • the obtained gene is cDNA of the urate transporter gene, i.e., a gene product encoded by the cDNA is the urate transporter.
  • the ability to transport (uptake) uric acid into cells can be confirmed by introducing cRNA (complementary RNA) prepared from the obtained URAT1 cDNA into oocyte to express, and measuring the uptake of a substrate into the cells by the conventional uptake experiment using uric acid as the substrate (Sekine, T. et al., Biochem. Biophis. Res. Commun., 251:586-591, 1998).
  • transport property and substrate specificity of URAT1 can be examined by applying the similar uptake experiment to expressing cells.
  • URAT1 for example, the property that URAT1 performs the transport with time dependency, substrate selectivity and pH dependency of URAT1 can be examined by applying the similar uptake experiment to the expressing cells.
  • Homologous genes and chromosomal genes derived from the different tissues or different organisms can be isolated by screening appropriate cDNA libraries or genomic DNA libraries made from the different gene sources using cDNA of the obtained URAT1 gene.
  • the gene can be isolated from the cDNA library by the conventional PCR method using synthetic primers designed on the basis of the information of the disclosed base sequence of the gene of the present invention (the base sequence represented by SEQ ID NO:1 or a part thereof).
  • DNA libraries such as cDNA library and genomic DNA library can be prepared by the methods described in, for example, “Sambrook, J., Fritsh E. F., and Maniatis, T., “Molecular Cloning” (published by Cold Spring Harbor Laboratory Press in 1989)”. Or when there is a commercially available library, it may be used.
  • the genomic DNA library is screened using the obtained URAT1 gene cDNA, and the obtained clones are analyzed. Or the structure may be searched on the basis of the disclosed information of the human genome analysis results using a homology search program.
  • the urate transporter (URAT1) of the present invention can be produced by gene recombination technology using cDNA which encodes the urate transporter.
  • cDNA DNA which encodes the urate transporter
  • Expression systems (host vector system) for producing the polypeptide include the expression systems of bacteria, yeast, insect cells and mammalian cells. Among these, to obtain the functional protein, it is desirable to use the insect cells and the mammalian cells.
  • an expression vector is constructed by inserting DNA which encodes the urate transporter in the downstream of an appropriate promoter (e.g., SV40 promoter, LTR promoter, elongation 1 ⁇ promoter and the like) in an appropriate expression vector (e.g., retroviral vector, papilloma virus vector, vaccinia virus vector, SV40 type vector and the like).
  • an appropriate expression vector e.g., retroviral vector, papilloma virus vector, vaccinia virus vector, SV40 type vector and the like.
  • the mammalian cells as the hosts include cell lines such as monkey COS-7 cells, Chinese hamster CHO cells, human HeLa cells and primary culture cells derived from renal tissues, LLC-PK1 cells derived from swine kidney, OK cells derived from opossum kidney, and proximal convoluted tubule S1, S2 and S3 cells derived from mouse.
  • cell lines such as monkey COS-7 cells, Chinese hamster CHO cells, human HeLa cells and primary culture cells derived from renal tissues, LLC-PK1 cells derived from swine kidney, OK cells derived from opossum kidney, and proximal convoluted tubule S1, S2 and S3 cells derived from mouse.
  • the cDNA which encodes the urate transporter URAT1 it is possible to use the cDNA having the base sequence shown in the sequence 1, and further it is possible to design DNA corresponding to the amino acid sequence and use the DNA which encodes the polypeptide without being limited to the above cDNA.
  • 1 to 6 codons which encodes one amino acid are known, and the codon used may be optionally selected, but it is possible to design the sequence with high expression by considering use frequency of codons in the host utilized for the expression.
  • the DNA with the designed sequence can be acquired by chemical synthesis of DNA, fragmentation and bind of the above cDNA, partial modification of the base sequence and the like.
  • the artificial partial modification and mutagenesis can be carried out by site specific mutagenesis methods (Mark, D. F. et al., Proc. Natl. Acad. Sci. USA, 18:5662-5666, 1984) utilizing primers including synthetic oligonucleotides which encode the desired modification.
  • nucleotides which hybridize with the urate transporter gene of the present invention under a stringent condition can be used as probes to detect the urate transporter gene, and further can be used, for example, as antisense oligonucleotides, ribozymes and decoys to modulate the expression of the urate transporter.
  • nucleotides it is possible to use, for example, the nucleotides typically comprising the partial sequence of consecutive 14 or more bases or the complementary sequence thereof in the base sequence represented by SEQ ID NO:1.
  • the longer sequence e.g., the sequence of 20 or more bases or 30 or more bases may be used.
  • the urate transporter of the present invention or the polypeptide having immunological equivalence thereto, it is possible to acquire antibodies thereof, and the antibodies can be utilized for the detection and the purification of the urate transporter.
  • the antibody can be produced by using the urate transporter of the invention, a fragment thereof, or a synthetic peptide having the partial sequence thereof and the like as an antigen.
  • the polyclonal antibody can be produced by the conventional method in which the antigen is inoculated to the host animal (e.g., rat or rabbit) and immunized serum is collected, and the monoclonal antibody can be produced by the conventional technology such as a hybridoma method.
  • the present invention provides a screening method of a substance having uricosuric accelerating action.
  • the protein of the invention works for transporting uric acid into the cells and is deeply involved in the reabsorption of uric acid.
  • FIGS. 6, 8, 9 and 10 it is possible to quantify the accelerating or inhibiting action for uric acid uptake of the screening substance in the system where the protein of the invention is expressed, by adding uric acid to the system, further adding the screening substance thereto, and comparing a uric acid uptake amount with that in the case with no addition of the screening substance.
  • the substances clinically used as uricosuric accelerators have remarkably inhibited the uptake of uric acid in the above experimental system, and thus, it is shown that it become possible to screen the uricosuric accelerating action of the screening substance in this system.
  • the cells used in this screening system the cells are not limited to oocytes used in the following experiments, and it is possible to use various living cells as long as the cells can express the protein of the invention.
  • the present invention provides the method for screening substances having uricosuric regulating action using the protein of the invention.
  • the uricosuric regulating actions there are the uricosuric accelerating action and the uricosuric inhibiting action, and those having the uricosuric accelerating action are preferable for the treatment/prevention of hyperuricemia and gout.
  • the preferable uricosuric regulating action includes the uricosuric accelerating action.
  • the present invention provides uricosuric regulators screened by the above screening method.
  • the preferable uric acid regulator includes a uricosuric accelerators.
  • the uricosuric regulator screened by the method of the invention can regulate the uptake of uric acid by the urate transporter involved in the urate transport in the kidney, and therefore can be used as an active ingredient of the medicines for the treatment/prevention of various diseases associated with the reabsorption of uric acid such as hyperuricemia and gout.
  • a primer specific for the 5′ upstream region of the predicted initiation codon was made using 28 bases, and the isolation of this novel gene was attempted by 3′-RACE (3′-rapid amplification of cDNA ends) method using messenger RNA derived from various tissues of human.
  • 3′-RACE 3′-rapid amplification of cDNA ends
  • a monoclone was obtained by the 3′-RACE method using human kidney messenger RNA.
  • a single band obtained by PCR method was subcloned in pCRII-TOPO vector using TA cloning method, and further subcloned in pcDNA 3.1(+) vector which was the expression vector.
  • a novel cDNA (URAT1 cDNA) which has urate transport activity was obtained (for analysis of transport function, see the followings.).
  • URAT1 gene was analyzed in various tissues of human (Northern blotting) (FIG. 1).
  • Full length URAT1 cDNA was labeled with 32 P-dCTP, and using this as a probe, hybridization was carried out using filters (manufactured by Clontech) blotting RNA extracted from various human tissues.
  • the hybridization was carried out overnight in a hybridization solution comprising the labeled full length URAT1 cDNA, and the filters were washed with 0.1 ⁇ SSC comprising 0.1% SDS at 65° C.
  • 0.1 ⁇ SSC comprising 0.1% SDS at 65° C.
  • cRNA RNA complementary to cDNA
  • T7 RNA polymerase see Sekine, T., et al., J. Biol. Chem., 272:18526-18529, 1997.
  • URAT1 is the exchanger of uric acid and monocarboxylic acid. Pyrazinamide which is an antituberculous drug is metabolized to become pyrazine carboxylic acid, which is then excreted into urine, whereas it is said to facilitate the reabsorption of uric acid.
  • the above result shows that as a result of the exchange of uric acid and pyrazine carboxylic acid in URAT1, the uptake of uric acid is facilitated. Accordingly the mechanism to cause hyperuricemia has been demonstrated which is a side effect of pyrazinamide which is the antituberculous drug.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070010670A1 (en) * 2004-11-29 2007-01-11 Japan Tobacco Inc. Nitrogen-containing fused ring compounds and use thereof
US20140256748A1 (en) * 2011-11-03 2014-09-11 Ardea Biosciences, Inc. 3,4-di-substituted pyridine compound, methods of using and compositions comprising the same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1698348A4 (de) * 2003-11-14 2008-02-27 Human Cell Systems Inc Mittel zur behandlung/prävention von gefässerkrankungen und hypertonie und untersuchungsverfahren
JP4643566B2 (ja) 2004-03-01 2011-03-02 独立行政法人科学技術振興機構 Ｎ−アシルヒドラゾンのアリル化方法
JP5574357B2 (ja) * 2008-06-04 2014-08-20 ジェイファーマ株式会社 腎臓尿酸トランスポーター
WO2010150525A1 (ja) 2009-06-22 2010-12-29 国立大学法人東京大学 尿酸トランスポーター、並びに、尿酸輸送関連疾患素因及び炎症関連疾患素因の評価方法及び評価キット、検査体及び薬
JP6628226B2 (ja) 2014-01-17 2020-01-08 洋孝 松尾 痛風発症素因の評価方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040034192A1 (en) * 2000-01-06 2004-02-19 Seishi Kato Human proteins having hyprophobic domains and dnas encoding these proteins
US20060035315A1 (en) * 2000-02-25 2006-02-16 Incyte Genomics, Inc. Transporters and ion channels

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040034192A1 (en) * 2000-01-06 2004-02-19 Seishi Kato Human proteins having hyprophobic domains and dnas encoding these proteins
US20060035315A1 (en) * 2000-02-25 2006-02-16 Incyte Genomics, Inc. Transporters and ion channels

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070010670A1 (en) * 2004-11-29 2007-01-11 Japan Tobacco Inc. Nitrogen-containing fused ring compounds and use thereof
US20140256748A1 (en) * 2011-11-03 2014-09-11 Ardea Biosciences, Inc. 3,4-di-substituted pyridine compound, methods of using and compositions comprising the same
US10047050B2 (en) * 2011-11-03 2018-08-14 Ardea Biosciences, Inc. 3,4-di-substituted pyridine compound, methods of using and compositions comprising the same
US10570095B2 (en) 2011-11-03 2020-02-25 Ardea Biosciences, Inc. 3,4-di-substituted pyridine compound, methods of using and compositions comprising the same

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CA2456172A1 (en) 2003-04-03
DE60225699T2 (de) 2009-04-23
EP1428880B1 (de) 2008-03-19
CA2456172C (en) 2011-04-12
JP2003093067A (ja) 2003-04-02
JP3824899B2 (ja) 2006-09-20
AU2002325545B2 (en) 2007-11-01
WO2003027287A1 (fr) 2003-04-03
ATE389720T1 (de) 2008-04-15
HK1066241A1 (en) 2005-03-18
EP1428880A1 (de) 2004-06-16
EP1428880A4 (de) 2005-03-30
US20070117162A1 (en) 2007-05-24
DE60225699D1 (de) 2008-04-30

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