| 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)
横山 宏和 杏林大学, 医学部, 助手
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥39,910,000 (Direct Cost: ¥30,700,000、Indirect Cost: ¥9,210,000)
Fiscal Year 2004: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2003: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
Fiscal Year 2002: ¥21,190,000 (Direct Cost: ¥16,300,000、Indirect Cost: ¥4,890,000)
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| Keywords | Familial renal hypouricemia / Hyperuricemia / URAT1 / PDZK1 / Organic anion transporter / renal stones / genetic factor / gout / 近位尿細管性アシドーシス / シスチン尿症 / BAT1 / rBAT / ナトリウム / 重炭酸イオン共輸送体 / 環境因子 / ゲノム / 尿酸トランスポーター / 尿酸 / 特発性低尿酸血症 / イーストツーハイブリド法 / PDZK 1 / ベンズプロマロン / ベンズブロマロン |
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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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