Identification of urate transporter, genetic analysis of renal hypouricemia and the development of anti-hyperuricemia drug

• Project/Area Number: 14370318
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Nagoya University
• Principal Investigator: NIWA Toshimitsu Nagoya University, University Hospital, Associate Professor, 医学部附属病院, 助教授 (20208268)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥14,000,000 (Direct Cost: ¥14,000,000); Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000); Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000); Fiscal Year 2002: ¥9,500,000 (Direct Cost: ¥9,500,000)
• Keywords: renal tubule / urate transport / renal hypouricemia / genetic analysis / anti-hyperuricemia drug / 尿酸 / トランスポーター / URAT1

Research Abstract

We have succeeded in cloning of urate transporter (URAT1) that is involved in the reabsorption of urate in the tubules of human kidneys, and demonstrated that the transcript protein shows the function of urate transport (Nature 417(6887):447-452,2002). We produced antibody against the protein, and demonstrated that the protein is expressed in the renal tubules. Patients with renal hypouricemia showed homo mutation in the gene of URAT1,and thus URAT1 is a gene responsible for renal hypouricemia. This gene is a target molecule for the development of anti-hyperuricemia drugs.
We studied the association between single nucleotide polymorphism(SNP) mutation of URAT1 and the serum levels of urate. We analyzed mutations of URAT1 [Ex3(C217;Thr→Met) (C→T)とEx4(G258A;Trp→stop)(G→A)] by using Light-Cycler in 164 healthy subjects who had taken health checkup at our hospital. We found that for Ex3 mutation(C217;Thr→Met)(C→T), one subject showed hetero mutation, and none showed homo mutation, and that for Ex4(G258A;Trp→stop)(G→A), 3 subjects showed hetero mutation, and none showed homo mutation. The serum levels of urate in the subjects with hetero mutation were 4.1 mg/dl for Ex3 mutation, and 5.3 mg/dl, 4.2 mg/dl, and 4.5 mg/dl for E4 mutation. Thus, the hetero mutation of URAT1 was not associated with hypouricemia.

Research Products

• [Journal Article] Interactions of human organic anion transporters with diuretics. (2004)
  • Author(s): Hasannejad H, Takeda M, ……Niwa T, Endou H
  • Journal Title: Pharmacol Exp The 308(3) Pages: 1021-1029
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs. (2004)
  • Author(s): Hasannejad H, Takeda M, ‥Niwa T, ‥Endou H.
  • Journal Title: Eur J Pharmacol. 499(1-2) Pages: 45-51
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interactions of human organic anion transporters with diuretics. (2004)
  • Author(s): Hasanne jad 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
  • Journal Title: J Pharmacol Exp The 308(3) Pages: 1021-1029
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs. (2004)
  • Author(s): Hasanne jad H, Takeda M, Narikawa S, Huang XL, Enomoto A, Taki K, Niwa T, Jung SH, Onozato ML, Tojo A, Endou H.
  • Journal Title: Eur J Phannacol. 499(1-2) Pages: 45-51
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interactions of human organic anion transporters with diuretics. (2004)
  • Author(s): Hasannejad H, Takeda M, Taki K, Jung SH, Babu E, Jutabha P, Khamdang S, Aleboyeh M, Onozato ML, Tojo A, Enomoto A, Anzai N, Narikawa S, Huang XL, Niwa T, Endou H
  • Journal Title: Pharmacol Exp The 308(3) Pages: 1021-1029
• [Journal Article] Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs. (2004)
  • Author(s): Hasannejad H, Takeda M, Narikawa S, Huang XL, Enomoto A, Taki K, Niwa T, Jung SH, Onozato ML, Tojo A, Endou H.
  • Journal Title: Eur.J.Pharmacol. 499(1-2) Pages: 45-51
• [Journal Article] Interactions of human organic anion as well as cation transporters with indoxyl sulfate. (2003)
  • Author(s): Enomoto A, Takeda M, ……Niwa T, Endou H
  • Journal Title: Eur J Pharmacol. 466 Pages: 13-20
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interactions of human organic anion as well as cation transporters with indoxyl sulfate. (2003)
  • Author(s): Enomoto A, Takeda M, Taki K, Takayama F, Noshiro R, Niwa T, Endou H
  • Journal Title: Eur J Phannacol. 466 Pages: 13-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular identification of a renal urate anion exchanger that regulates blood urate levels. (2002)
  • Author(s): Enomoto A, Kimura H, …Niwa T, Kanai Y, Endou H
  • Journal Title: Nature 417(6887) Pages: 447-452
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of organic anion transporters in the tubular transport of indoxyl dulfate and the induction of its nephrotoxicity. (2002)
  • Author(s): Enomoto A, Takeda M, ………Endou H, Niwa T
  • Journal Title: J Am Soc Nephrol 13 Pages: 1711-1720
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular identification of a novel carnitine transporter specific to human testis : Insights into the mechanism of carnitine recognitiio (2002)
  • Author(s): Enomoto A, Wempe MF, …Niwa T, ………Endou H
  • Journal Title: J Biol Chem 277(39) Pages: 36262-36271
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Molecular identification of a renal urate anion exchanger that regulates blood urate levels. (2002)
  • Author(s): Enomoto A, Kimira H, Chairoungdua A, Shigeta Y, Jutabha P, Ho Cha S, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Ehdou H
  • Journal Title: Nature 417(6887) Pages: 447-452
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of organic anion transporters in the tubular transport of indoxyl dulfate and the induction of its nephrotoxicity. (2002)
  • Author(s): Enomoto A, Takeda M, Tojo A, Sekine T, Cha SH, Khamdang S, Takayama F, Aoyama I, Nakamura S, Endou H, Niwa T
  • Journal Title: J Am Soc Nephrol 13 Pages: 1711-1720
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Molecular identification of a novel camitine transporter specific to human testis : Insights into the mechanism of camitine recognition. (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
  • Journal Title: J Biol Chem 277(39) Pages: 36262-26271
  • Description: 「研究成果報告書概要(欧文)」より