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2012 Fiscal Year Final Research Report

Efficient chemical library screening for WNK signaling inhibitors byinhibiting WNK-SPAK interaction

Research Project

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Project/Area Number 23659439
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Kidney internal medicine
Research InstitutionTokyo Medical and Dental University

Principal Investigator

UCHIDA Shinichi  東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (50262184)

Project Period (FY) 2011 – 2012
Keywords水 / 電解質代謝学
Research Abstract

We focused on the With-no-lysine kinases (WNK) signaling cascade which has a pivotal role in regulating blood pressure. Agents that inhibit this signal cascade could be a new class of antihypertensive drugs. We sought to discover inhibitors of WNK-SPAK binding by screening chemical compounds that disrupt the binding. For this purpose, we developed a high-throughput screening method using fluorescent correlation spectroscopy. As a result of screening 17,000 compounds, we discovered two novel compounds that reproducibly disrupted the binding of WNK to SPAK. We then performed the modification of the seed compounds, and obtained novel compounds that exhibit the higher inhibitory activity.

  • Research Products

    (48 results)

All 2012 2011 Other

All Journal Article (18 results) (of which Peer Reviewed: 18 results) Presentation (20 results) Book (9 results) Remarks (1 results)

  • [Journal Article] Involvement of aquaporin-7 in the cutaneous primary immune response through modulation of antigen uptake and migration in dendritic cells2012

    • Author(s)
      Hara-Chikuma M, Sugiyama Y, Kabashima K, Sohara E, Uchida S, Sasaki S, Inoue S, Miyachi Y
    • Journal Title

      FASEB J

      Volume: 26 Pages: 211-8

    • Peer Reviewed
  • [Journal Article] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates itsubiquitination2012

    • Author(s)
      Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Oi K, Rai T, Sasaki S, Uchida S
    • Journal Title

      Biochem. Biophys. Res. Commun

      Volume: 425 Pages: 456-61

    • Peer Reviewed
  • [Journal Article] A new role for aquaporin 7 in insulinsecretion2012

    • Author(s)
      Louchami K, Best L, Brown P, Virreira M, Hupkens E, Perret J, Devuyst O, Uchida S, Delporte C, Malaisse WJ, Beauwens R, Sener A
    • Journal Title

      Cell Physiol. Biochem

      Volume: 29 Pages: 65-74

    • Peer Reviewed
  • [Journal Article] ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney2012

    • Author(s)
      Naguro I, Umeda T, Kobayashi Y, Maruyama J, Hattori K, Shimizu Y, Kataoka K, Kim-Mitsuyama S, Uchida S, Vandewalle A, Noguchi T, Nishitoh H, Matsuzawa A, Takeda K, Ichijo H
    • Journal Title

      Nat. Commun

      Volume: 3 Pages: 1285

    • Peer Reviewed
  • [Journal Article] Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice2012

    • Author(s)
      Nishida H, Sohara E, Nomura N, Chiga M, Alessi DR, Rai T, Sasaki S, Uchida S
    • Journal Title

      Hypertension

      Volume: 60 Pages: 981-90

    • Peer Reviewed
  • [Journal Article] Accumulation of autofluorescent storage material in brain is accelerated by ischemia in chloride channel 3 gene-deficient mice2012

    • Author(s)
      Ohtaki H, Ohara K, Song D, Miyamoto K, Tsumuraya T, Yofu S, Dohi K, Tanabe S,Sasaki S, Uchida S, Matsunaga M, Shioda S
    • Journal Title

      J. Neurosci. Res

      Volume: 90 Pages: 2163-72

    • Peer Reviewed
  • [Journal Article] A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCC co-transporters in vivo2012

    • Author(s)
      Oi K, Sohara E, Rai T, Misawa M, ChigaM, Alessi DR, Sasaki S, Uchida S
    • Journal Title

      Biol.Open

      Volume: 1 Pages: 120-7

    • Peer Reviewed
  • [Journal Article] Uchida S.Effect of heterozygous deletion of WNK1 on the WNK-OSR1/ SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels2012

    • Author(s)
      Susa K, Kita S, Iwamoto T, Yang SS, LinSH, Ohta A, Sohara E, Rai T, Sasaki S, Alessi DR
    • Journal Title

      Clin. Exp. Nephrol

      Volume: 16 Pages: 530-8

    • Peer Reviewed
  • [Journal Article] Uchida S.WNK-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone.Biochem2012

    • Author(s)
      Susa K, Sohara E, Isobe K, Chiga M, RaiT, Sasaki S
    • Journal Title

      Biophys. Res. Commun

      Volume: 427 Pages: 743-7

    • Peer Reviewed
  • [Journal Article] Does a β2-adrenergic receptor-WNK4-Na-Cl co-transporter signal cascade exist in the in vivo kidney?2012

    • Author(s)
      Uchida S, Chiga M, Sohara E, Rai T, Sasaki S
    • Journal Title

      Nat. Med

      Volume: 18 Pages: 1324-5

    • Peer Reviewed
  • [Journal Article] Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on theWNK-OSR1/SPAK kinase cascade2011

    • Author(s)
      Chiga M, Rafiqi FH, Alessi DR, Sohara E, Ohta A, Rai T, Sasaki S, Uchida S
    • Journal Title

      J. Cell Sci

      Volume: 124 Pages: 1391-5

    • Peer Reviewed
  • [Journal Article] Impaired phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter by oxidative stress-responsive kinase-1deficiency manifests hypotension and Bartter-like syndrome2011

    • Author(s)
      Lin SH, Yu IS, Jiang ST, Lin SW, Chu P, Chen A, Sytwu HK, Sohara E, Uchida S, Sasaki S, Yang SS
    • Journal Title

      Proc. Natl. Acad. Sci. U S A

      Volume: 108 Pages: 17538-43

    • Peer Reviewed
  • [Journal Article] Uchida S.Regulation of WNK1 kinase by extracellular potassium2011

    • Author(s)
      Naito S, Ohta A, Sohara E, Ohta E, RaiT, Sasaki S
    • Journal Title

      Clin. Exp. Nephrol

      Volume: 15 Pages: 195-202

    • Peer Reviewed
  • [Journal Article] Generation and analyses of R8L barttin knockin mouse2011

    • Author(s)
      Nomura N, Tajima M, Sugawara N, Morimoto T, Kondo Y, Ohno M, Uchida K, Mutig K, Bachmann S, Soleimani M, Ohta E, Ohta A, Sohara E, Okado T, Rai T, JentschTJ, Sasaki S, Uchida S
    • Journal Title

      Am. J. Physiol. Renal. Physiol

      Volume: 301 Pages: F297-307

    • Peer Reviewed
  • [Journal Article] Dexamethasone increases the phosphorylation of nephrin in culturedpodocytes2011

    • Author(s)
      Ohashi T, Uchida K, Uchida S, SasakiS, Nitta K
    • Journal Title

      Clin. Exp. Nephrol

      Volume: 15 Pages: 688-93

    • Peer Reviewed
  • [Journal Article] Immunolocalization of WNK4 in mouse kidney2011

    • Author(s)
      Ohno M, Uchida K, Ohashi T, Nitta K, Ohta A, Chiga M, Sasaki S, Uchida S
    • Journal Title

      Histochem. Cell Biol

      Volume: 136 Pages: 25-35

    • Peer Reviewed
  • [Journal Article] A minor role of WNK3 in regulating phosphorylation of renal NKCC2 and NCCco-transporters in vivo2011

    • Author(s)
      Oi K, Sohara E, Rai T, Misawa M, ChigaM, Alessi DR, Sasaki S, Uchida S
    • Journal Title

      Biology Open

      Volume: 1(2) Pages: 120-7

    • Peer Reviewed
  • [Journal Article] Acute insulin stimulation induces phosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney2011

    • Author(s)
      Sohara E, Rai T, Yang SS, Ohta A, NaitoS, Chiga M, Nomura N, Lin SH, VandewalleA, Ohta E, Sasaki S, Uchida S
    • Journal Title

      PLoS One

      Volume: 6 Pages: e24277

    • Peer Reviewed
  • [Presentation] Role of WNK kinases in the blood pressure regulation2012

    • Author(s)
      Uchida S
    • Organizer
      Taiwan Society of Nephrology 2012
    • Place of Presentation
      China Medical University, Taichung, Taiwan
    • Year and Date
      20121200
  • [Presentation] Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination2012

    • Author(s)
      Hossain Khan MZ, Sohara E, Ohta A, Chiga M, Inoue Y, Isobe K, Wakabayashi M, Naito S, Oi K, Rai T, Sasaki S, Uchida S
    • Organizer
      The 45th Annual meeting of American Society of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] Development of sandwich enzyme linked immunosorbent assay (ELISA) formeasurement of urinary total and phosphorylated Na-Cl cotransporter (NCC) protein2012

    • Author(s)
      Isobe K, Sohara E, Rai T, Sasaki S, Uchida S
    • Organizer
      The 45th Annual meeting of American Society of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] Chemical library screening for direct SPAK inhibitors by a newly developed ELISA system2012

    • Author(s)
      Kikuchi E, Mori T, Isobe K, Sohara E,Rai T, Sasaki S, Uchida S
    • Organizer
      The 45th Annual Meeting of AmericanSociety of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] Generation and analysis of WT-WNK4 transgenic mice revealed the physiological role of WNK42012

    • Author(s)
      Mori T, Sohara E, Rai T, Sasaki ,Uchida S
    • Organizer
      The 45th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] Hereditary nephrogenic diabetes insipidus (NDI) in Japanese patients: Analysis of 73 families2012

    • Author(s)
      Sasaki S, Chiga M, Kikuchi, EUchida S
    • Organizer
      The 45th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] WNK4-OSR1/SPAK-NCC signal cascade has circadian rhythm dependent on aldosterone2012

    • Author(s)
      Susa K, Sohara E, Isobe K, Chiga M, RaiT, Sasaki S, Uchida S
    • Organizer
      The 45th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] Dietary salt intake and angiotensin II regulates WNK-SPAK-NKCC1 phosphorylation cascade in mouse aorta2012

    • Author(s)
      Zeniya M, Sohara E, Oi K, Chiga M, Susa K, Mori T, Rai T, Sasaki S, Uchida S
    • Organizer
      The 45th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      San Diego (USA)
    • Year and Date
      20121100
  • [Presentation] Chemical library screening for drugs to correct intracellular mislocalization of R8L mutant barttin2012

    • Author(s)
      Uchida S
    • Organizer
      2012 International Ion Channel Conference
    • Place of Presentation
      The New world of anion and cation channels. Jeju, Korea
    • Year and Date
      20120800
  • [Presentation] Generation and analyses of AQP11 BAC transgenic mice2011

    • Author(s)
      Inoue Y, Sohara E, Kobayashi K, Rai T, Ishibashi K, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Development of new systems to measure total and phosphorylated Na-Cl cotransporter(NCC)protein in human urine2011

    • Author(s)
      Isobe K, Ohta A, Sohara E, Rai T, SasakiS, Uchida S.
    • Organizer
      The 44th Annual Meeting of AmericanSociety of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Urinary excretion of Na-Cl Cotransporter in exosomes is increased by high salt diet as well as low salt diet2011

    • Author(s)
      Kahn MZH, Sohara E, Ohta A, Naito S, Chiga M, Rai T, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] CFTR is highly expressed in the cyst-lining epithelial cells of the AQP11knockout mouse kidney2011

    • Author(s)
      Kobayashi K, Uchida S, Sasaki S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] High throughput screening of drugs that inhibit WNK-OSR1/SPAK signaling cascade2011

    • Author(s)
      Mori T, Ohta A, Sohara E, Rai T, SasakiS, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Increased Na-Cl cotransporter phosphorylation in hyperinsulinemic db/db mice is regulated by insulin/PI3K pathway2011

    • Author(s)
      Nishida H, Sohara E, Alessi DR, NomuraN, Rai T, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of AmericanSociety of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Chemical library screening for drugs to correct intracellular mislocalization of R8L mutant barttin2011

    • Author(s)
      Nomura N, Naito S, Sohara E, Rai T, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Renal phenotype of WNK3 knockout mouse2011

    • Author(s)
      Oi K, Sohara E, Rai T, Chiga M, AlessiDR, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Acute insulin stimulation inducesphosphorylation of the Na-Cl cotransporter in cultured distal mpkDCT cells and mouse kidney2011

    • Author(s)
      Sohara E, Rai T, Yang SS, Ohta A, Chiga M, Nomura N, Lin SH, Vandewalle A, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] WNK-OSR1/SPAK-SLC12A phosphorylation cascade in the WNK1 (+/-) mice2011

    • Author(s)
      Susa K, Ohta A, Sohara E, Rai T, KitaS, Iwamoto T, Alessi DR, Sasaki S, UchidaS
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Presentation] Increased protein abundance of the mutant WNK4 may be a cause of the increased WNK4 kinase activity in the mouse model of pseudohypoaldosteronism type II2011

    • Author(s)
      Wakabayashi M, Naito S, Sohara E, RaiT, Sasaki S, Uchida S
    • Organizer
      The 44th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      Philadelphia (USA)
    • Year and Date
      20111100
  • [Book] 細胞工学2012

    • Author(s)
      内田信一
    • Total Pages
      558-564
  • [Book] 脱水腎と透析2012

    • Author(s)
      笠木祐里,内田信一
    • Total Pages
      77-81
  • [Book] 日本臨床別冊腎臓症候群(上)2012

    • Author(s)
      高橋大栄,内田信一
    • Total Pages
      790-793
  • [Book] 遺伝子医学MOOK19トランスポートソーム生体膜輸送機構の全体像に迫る2011

    • Author(s)
      須佐紘一郎,内田信一
    • Total Pages
      260-264
  • [Book] 医学のあゆみ2011

    • Author(s)
      三澤慕子,内田信一
    • Total Pages
      792-793
  • [Book] 内分泌・糖尿病・代謝内2011

    • Author(s)
      若林麻衣,内田信一
    • Total Pages
      306-313
  • [Book] バソプレシンと病態形成の関わり2011

    • Author(s)
      野村尚弘,内田信一
    • Total Pages
      165-170
    • Publisher
      メディカルレビュー社
  • [Book] トランスポートソームの世界2011

    • Author(s)
      日比野浩,内田信一,野村尚弘
    • Total Pages
      136-141
    • Publisher
      京都廣川書店
  • [Book] 偽性低アルドステロン症II型

    • Author(s)
      森崇寧,内田信一
    • Total Pages
      155-159
  • [Remarks] 東京医科歯科大学腎臓内科学ホーム

    • URL

      http://www.tmd.ac.jp/grad/kid/kid-J.htm

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Published: 2014-09-25  

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