Analysis of WNK kinases and the molecular pathophysiology of hypertension

• Project/Area Number: 18590883
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: RAI Tatemitsu Tokyo Medical and Dental University, 医学部附属病院, 准教授 (80334431)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,100,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥600,000); Fiscal Year 2008: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: WNKキナーゼ / 偽性低アルドステロン症II型 / ノックインマウス / ノックアウトマウス / Na-Cl共輸送体 / OSR1 / SPAK / 高血圧 / 遺伝子改変マウス / 偽性低アルドステロン血症II型 / 偽性低アルドステオン症II型 / claudin / MDCK細胞

Research Abstract

高血圧を示す遺伝性疾患である偽性低アルドステロン症II型(PHAII)の原因遺伝子WNK キナーゼの解析を通じて、腎臓においてWNK-OSR, SPAK-NCCリン酸化シグナル伝達系という新規の血圧調節系が存在することを発見した。この系は塩分の摂取量の増減に応じて腎臓遠位尿細管での塩分再吸収を調節することで血圧を上下させる。さらにこの系の破綻が原因となった高血圧の発症機序も明らかにした。

Research Products

• [Journal Article] Dietarysalt regulates the phosphorylation ofOSR1/SPAK kinases and the sodiumchloride cotransporter throughaldosterone (2008)
  • Author(s): Chiga M, Rai T, Yang SS, Ohta A,Takizawa T, Sasaki S, Uchida S
  • Journal Title: Kidney Int 74 Pages: 1403-1409
• [Journal Article] AKAP220 colocalizes with AQP2 in the inner medullary collecting ducts. (2008)
  • Author(s): Okutsu R, et al
  • Journal Title: Kidney Int 74 Pages: 1429-1433
  • Peer Reviewed
• [Journal Article] Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone. (2008)
  • Author(s): Chiga M, et al
  • Journal Title: Kidney Int 74 Pages: 1403-1409
  • Peer Reviewed
• [Journal Article] A familial case of mitochondrial disease resembling Alport syndrome. (2008)
  • Author(s): Fujii H, et al
  • Journal Title: Clin Exp Nephrol 12 Pages: 159-163
  • Peer Reviewed
• [Journal Article] Molecular pathogenesis ofpseudohypoaldosteronism type II : generation and analysis of a Wnk4^<D561A/+> knockin mouse model (2007)
  • Author(s): Yang SS, Morimoto T, Rai T, Chiga M,Sohara E, Ohno M, Uchida K, Lin SH,Moriguchi T, Shibuya H, Kondo Y, SasakiS, Uchida S
  • Journal Title: Cell Metab 5(5) Pages: 331-44
• [Journal Article] Barttin binds to the outerlateral surface of the ClC-K2 chloride channel (2007)
  • Author(s): Tajima M, Hayama A, Rai T, Sasaki S,Uchida S
  • Journal Title: Biochem Biophys Res Commun 362(4) Pages: 858-64
• [Journal Article] Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4 (D561A/+)knockin mouse model (2007)
  • Author(s): Yang SS, et. al.
  • Journal Title: Cell Metab 5 Pages: 331-344
  • Peer Reviewed
• [Journal Article] Barttin binds to the outer Iateral surface of the CIC-K2 chloride channel (2007)
  • Author(s): Fajima M, et. al.
  • Journal Title: Biochem Biophys Res Commun 362 Pages: 858-864
  • Peer Reviewed
• [Journal Article] Morphologic and functional-analysis of sperm and testes in Aquaporin 7 knockout mice (2007)
  • Author(s): Sohara E, et. al.
  • Journal Title: Fertil Steril 87 Pages: 671-676
  • Peer Reviewed
• [Journal Article] Overexpression ofhuman WNK1 increases paracellularchloride permeability and phosphorylation of claudin-4 in MDCKII cells (2006)
  • Author(s): Ohta A, Yang SS, Rai T, Chiga M, Sasaki S, Uchida S
  • Journal Title: Biochem Biophys Res Commun 349(2) Pages: 804-8
• [Journal Article] Pathogenesis andtreatment of autosomal-dominantnephrogenic diabetes insipidus caused by an aquaporin 2 mutation. (2006)
  • Author(s): Sohara E, Rai T, Yang SS, Uchida K,Nitta K, Horita S, Ohno M, Harada A,Sasaki S, Uchida S
  • Journal Title: Proc Natl Acad Sci U S A 103(38) Pages: 14217-22
• [Journal Article] Intracellular localization of ClCchloride channels and their ability toform hetero-oligomers (2006)
  • Author(s): Suzuki T, Rai T, Hayama A, Sohara E,Suda S, Itoh T, Sasaki S, Uchida S
  • Journal Title: J Cell Physiol 206(3) Pages: 792-8
• [Journal Article] Physiological roles of AQP7 in the kidney : Lessons from AQP7 knockout mice (2006)
  • Author(s): Sohara E, et al.
  • Journal Title: Biochim Biophys Acta 1758 Pages: 1106-1110
• [Journal Article] Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation (2006)
  • Author(s): Sohara E, et al.
  • Journal Title: Proc Natl Acad Sci USA 103 Pages: 14217-14222
• [Journal Article] Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells (2006)
  • Author(s): Ohta A, et al.
  • Journal Title: Biochem Biophys Res Commun 349 Pages: 804-808
• [Journal Article] Postnatal expression of KLF12 in the inner medullary collecting ducts of kidney and its trans-activation of UT-A1 urea transporter promoter (2006)
  • Author(s): Suda S, et al.
  • Journal Title: Biochem Biophys Res Commun 344 Pages: 246-252
• [Journal Article] Intracellular localization of CIC chloride channels and their ability to form hetero-oligomers (2006)
  • Author(s): Suzuki S, et al.
  • Journal Title: J Cell Physiol 206 Pages: 792-798
• [Journal Article] Polarized trafficking of the aquaporin-3 water channel is mediated by an NH2-terminal sorting signal (2006)
  • Author(s): Rai T
  • Journal Title: Am J Physiol Cell Physiol 290
• [Presentation] Na-Cl共輸送体(NCC)のリン酸化は WNK4-OSR1/SPAK-NCCリン酸化刺激伝達系を介し経口NaCl摂取量により制御される (2008)
  • Author(s): 千賀宗子, 頼建光, 他5名
  • Organizer: 第51回日本腎臓学会学術総会
  • Place of Presentation: 福岡
• [Presentation] 低浸透圧ストレスはOSR1/SPAKを持続的にリン酸化する (2008)
  • Author(s): 内藤省太郎, 頼建光, 他4名
  • Organizer: 第51回日本腎臓学会学術総会
  • Place of Presentation: 福岡
• [Presentation] WNK4ノックアウトマウス、作製と解析 (2008)
  • Author(s): 太田哲人, 頼建光, 他6名
  • Organizer: 第14回分子腎臓研究会
  • Place of Presentation: 東京
• [Presentation] Targeted Disruption of the Wnk4 GeneReduced the Phosphorylation ofOSR/SPAK and Na-Cl Cotransporter in Mice (2008)
  • Author(s): Akihito Ohta, Tatemitsu Rai, 他6名
  • Organizer: Renal Week 2008
  • Place of Presentation: Philadelphia
• [Presentation] WNK1 Activity to OSR1 in COS Cells IsRegulated Not by Hypotonicity but byLow Chloride (2008)
  • Author(s): Shotaro Naito, Tatemitsu Rai, 他5名
  • Organizer: Renal Week 2008
  • Place of Presentation: Philadelphia
• [Presentation] Na-Cl共輸送体(NCC)のリン酸化はWNK4-OSR1/SPAK-NCC リン酸化刺激伝達系を介し経口NaCl摂取量により制御される (2008)
  • Author(s): 千賀宗子, 他
  • Organizer: 第51回日本腎臓学会学術総会
  • Place of Presentation: 福岡
• [Presentation] Targeted disruption of the Wnk4 gene reduced the phosphorylation of OSR/SPAK and Na-Cl cotransporter in mice. (2008)
  • Author(s): Ohta A, et al
  • Organizer: Renal Week 2008
  • Place of Presentation: Philadelphia
• [Presentation] WNK1 activity to OSE1 in COS cells is regulated not by hypotonicity but by low chloride. (2008)
  • Author(s): Naito S, et al
  • Organizer: Renal Week 2008
  • Place of Presentation: Philadelphia
• [Presentation] Generation andanalysis of Wnk4D561A/+ knock-in mice (2007)
  • Author(s): Yang S, Rai T, 他11名
  • Organizer: ISN-Nature Genetics ForefrontsSymposium on Nephrogenetics : fromDevelopment to Physiology
  • Place of Presentation: Danvers USA
• [Presentation] Molecularpathogenesis of pseudohypoaldosteronism tupe II : generation and analysis of a Wnk4D561A/+knock-in mouse model (2007)
  • Author(s): Yang S, Rai T, 他11名
  • Organizer: 第50回日本腎臓学会学術総会
  • Place of Presentation: 浜松
• [Presentation] Molecularpathogenesis ofpseudohypoaldosteronism type II : analysis of a Wnk4D561A/+ knock-in mice (2007)
  • Author(s): Rai T, 他12名
  • Organizer: 第13回分子腎臓研究会
  • Place of Presentation: 東京
• [Presentation] Molecular pathogenesis of pseudohypoaldosteronism tupe II: generation and analysis of a Wnk4^<D561A/+>knock-in mouse model (2007)
  • Author(s): Yang S, et. al.
  • Organizer: 第50回日本腎臓学会学術総会
  • Place of Presentation: 浜松
• [Presentation] WNK1遺伝子の強発現により細胞間のchloride透過性は亢進し、claudin4はリン酸化が増加する (2006)
  • Author(s): 太田哲人, 頼建光, 他3名
  • Organizer: 第49回日本腎臓学会学術総会
  • Place of Presentation: 東京
• [Presentation] WNK1発現MDCKII細胞におけるparacellularのCl透過性とclaudin4のに関する検討 (2006)
  • Author(s): 太田哲人,頼建光, 他3名
  • Organizer: 第12回分子腎臓研究会
  • Place of Presentation: 東京