2004 Fiscal Year Final Research Report Summary
Development of novel anti-uricosuric agents based on the genomic strategy.
| Project/Area Number |
14207004
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Kyorin University |
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Principal Investigator |
ENDOU Hitoshi Kyorin University, Professors emeritus, 名誉教授 (20101115)
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| Co-Investigator(Kenkyū-buntansha) |
KANAI Yoshikatsu Kyorin University, School of Medicine, Professor, 医学部, 教授 (60204533)
HOSOYAMADA Makoto Kyorin University, School of Medicine, Lecturer, 医学部, 講師 (00291659)
ANZAI Naohiko Kyorin University, School of Medicine, Assistant, 医学部, 助手 (70276054)
IRIBE Yuji Kyorin University, School of Medicine, Assistant, 医学部, 助手 (20348618)
HIRATA Taku Kyorin University, School of Medicine, Assistant, 医学部, 助手 (60372918)
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| Project Period (FY) |
2002 – 2004
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| Keywords | Familial renal hypouricemia / Hyperuricemia / URAT1 / PDZK1 / Organic anion transporter / renal stones / genetic factor / gout |
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| Research Abstract |
Urate is the major inert end product of purine degradation in higher primates in contrast to most other mammals because of the genetic silencing of hepatic oxidative enzyme uricase. The kidney plays a dominant role in urate elimination ; it excretes 70% of the daily urate production. Therefore, it is important to understand renal urate handling mechanism because the underexcretion of urate has been implicated in the development of hyperuricemia that leads to gout. The urate transport systems exist in the proximal tubule but they are complicated because of their bidirectional transport and the species differences. Recently, we have identified the urate-anion exchanger URAT1 (SLC22A12) in the human kidney and found that defects in SLC22A12 lead to idiopathic renal hypouricemia. URAT1 is targeted by uricosuric and antiuricosuric agents that affect urate excretion. Molecular identification of urate transporting proteins will lead to the new drug development for hyperuricemia.
We also found
… More
that defects in SLC22A12 lead to idiopathic renal hypouricaemia (MIM number, 220150) and patients with such defects show a high fractional urate excretion such as 95 ± 10 % (normally <10%). These results indicate that URAT1 regulates blood urate level and vice versa, that is, to control blood urate levels, the URAT1 transport function should be regulated. A newly found genetic alteration in SLC22A12 from a patient of an idiopathic renal hypouricaemia has prompted us to consider the importance of the URAT1 extreme intracellular C-terminal region for its function. A 5-bp deletion near the URAT1 C-terminal end (1639-1643del) causes frameshift and the seven amino acids in the terminal sequences have changed into eight different amino acids. The URAT1 transport activity of this mutation is low in the Xenopus oocyte expression system. Interestingly, the PDZ binding motif at the C-terminal end of URAT1, which is known to participate in protein-protein interaction, disappears by this amino acid sequence modification.
In this study, we use the yeast two-hybrid approach to investigate the putative URAT1-associated proteins that modulate its transport function. We identify the multivalent PDZ domain-containing protein PDZK1 as an apparent partner of URAT1 in the human kidney. Moreover, we show a functional consequence of PDZK1/URAT1 interaction in transfected HEK293 cells, where URAT1 transport activities were increased by 1.4-fold by coexpression of PDZK1. We speculate that PDZK1 is a scaffolding protein that may be a physiological regulator of the function of URAT1. Less
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Author(s)
Tsuji K, Yamauchi K, Yang M, Jiang P, Bouvet M, Endo H, Kanai Y, Yamashita K, Moossa AR, Hoffman RM.
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Journal Title
Cancer Res. 66(1)
Pages: 303-306
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A novel missense mutation of SLC7A9 frequent in Japanese cystinuria cases affecting the C-terminus of the transporter.2006
Author(s)
Shigeta Y, Kanai Y, Chairoungdua A, Ahmed N, Sakamoto S, Matsuo H, Kim DK, Fujimura M, Anzai N, Mizoguchi K, Ueda T, Akakura K, Ichikawa T, Ito H, Endou H.
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Journal Title
Kidney Int. 69(7)
Pages: 1198-1206
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia.2005
Author(s)
Wakida N, Tuyen do G, Adachi M, Miyoshi T, Nonoguchi H, Oka T, Ueda O, Tazawa M, Kurihara S, Yoneta Y, Shimada H, Oda T, Kikuchi Y, Matsuo H, Hosoyamada M, Endou H, Otagiri M, Tomita K, Kitamura K.
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Journal Title
J Clin Endocrinol Metab. 90(4)
Pages: 2169-2174
Description
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[Journal Article] Functional characterization of rat organic anion transporter 5 (Slc22a19) at the apical membrane of renal proximal tubules.2005
Author(s)
Anzai N, Jutabha P, Enomoto A, Yokoyama H, Nonoguchi H, Hirata T, Shiraya K, He X, Cha SH, Takeda M, Miyazaki H, Sakata T, Tomita K, Igarashi T, Kanai Y, Endou H.
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Journal Title
J Pharmacol Exp Ther. 315(2)
Pages: 534-544
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Modulation of renal apical organic anion transporter 4 function by two PDZ domain-containing proteins.2005
Author(s)
Miyazaki H, Anzai N, Ekaratanawong S, Sakata T, Shin HJ, Jutabha P, Hirata T, He X, Nonoguchi H, Tomita K, Kanai Y, Endou H.
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Journal Title
J Am Soc Nephrol. 16(12)
Pages: 3498-3506
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Interactions of human organic anion transporters with diuretics.2004
Author(s)
Hasannejad H, Takeda M, Taki K, Shin HJ, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onozato ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H.
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Journal Title
J Pharmacol Exp Ther. 308(3)
Pages: 1021-1029
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The multivalent PDZ-containing protein PDZK1 regulates transport activity of renal urate-anion exchanger URAT1 via its C terminus.2004
Author(s)
Anzai N, Miyazaki H, Noshiro R, Khamdang S, Chairoungdua A, Shin HJ, Enomoto A, Sakamoto S, Hirata T, Tomita K, Kanai Y, Endou H.
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Journal Title
J Biol Chem. 279(44)
Pages: 45942-45950
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics.2003
Author(s)
Khamdang S, Takeda M, Babu E, Noshiro R, Onozato ML, Tojo A, Enomoto A, Huang XL, Narikawa S, Anzai N, Piyachaturawat P, Endou H.
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Journal Title
Eur J Pharmacol. 465(1-2)
Pages: 1-7
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule.2003
Author(s)
Jutabha P, Kanai Y, Hosoyamada M, Chairoungdua A, Kim do K, Iribe Y, Babu E, Kim JY, Anzai N, Chatsudthipong V, Endou H.
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Journal Title
J Biol Chem. 278(30)
Pages: 27930-27938
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters.2003
Author(s)
Babu E, Kanai Y, Chairoungdua A, Kim do K, Iribe Y, Tangtrongsup S, Jutabha P, Li Y, Ahmed N, Sakamoto S, Anzai N, Nagamori S, Endou H.
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Journal Title
J Biol Chem. 278(44)
Pages: 43838-43845
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The human T-type amino acid transporter-1 ; Characterization, gene organization, and chromosomal location.2002
Author(s)
Kim DK, Kanai Y, Matsuo H, Kim JY, Chairoungdua A, Kobayashi Y, Enomoto A, Cha SH, Goya T, Endou H.
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Journal Title
Genomics 79
Pages: 95-103
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of novel Na+-independent acidic amino acid transporter with structural similarity to the member of heterodimeric amino acid transporter family associated with unknown heavy chains.2002
Author(s)
Matsuo H, Kanai Y, Kim JY, Chairungdua A, Kim DK, Inatomi J, Shigeta, Y, Ishimine H, Chekuntode S, Tachampa K, Choi HW, Babu E, Fukuda J, Endou H.
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Journal Title
J Biol Chem. 277
Pages: 21017-21026
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular identification of a renal urate-anion exchanger that regulates blood urate levels.2002
Author(s)
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H.
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Journal Title
Nature 417
Pages: 447-452
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular identication of a novel carnitine transporter specific of human testis.2002
Author(s)
Enomoto A, Wempe MF, Tsuchida H, Shin HJ, Cha SH, Anzai N, Goto A, Sakamoto A, niwa T, Kanai Y, Anders MW, Endou H.
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Journal Title
J Biol Chem 277
Pages: 36262-26271
Description
「研究成果報告書概要(欧文)」より
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