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Development of SPAK kinase inhibitors

Research Project

Project/Area Number 25670406
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, 医歯(薬)学総合研究科, 教授 (50262184)

Project Period (FY) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords高血圧 / 創薬 / キナーゼ / ケミカルライブラリー / キナーゼ阻害薬
Outline of Final Research Achievements

WNK- STE20/SPS1-related proline-alanine-rich protein kinase (SPAK)-SLC12a transporters cascade regulates blood pressure through NaCl reabsorption in kidney and vasoconstriction. Therefore, drugs that inhibit this signal cascade could become new antihypertensive drugs that have dual effects as a diuretic and vasodilator. We sought to discover SPAK kinase inhibitors by screening chemical compounds and existing drugs. We developed a new screening system using enzyme-linked immunosorbent assay (ELISA) and screened over 20,000 small-molecule compounds. As a result of this screening effort, we discovered one small-molecule compound and Closantel, an antiparasitic agent, which inhibited SPAK-regulated NCC and NKCC1 phosphorylation and activation not only in vitro but also in cultured cell lines and in mice.

Report

(3 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • Research Products

    (24 results)

All 2015 2014 2013 Other

All Journal Article (17 results) (of which Peer Reviewed: 17 results,  Open Access: 1 results,  Acknowledgement Compliant: 1 results) Presentation (6 results) (of which Invited: 1 results) Remarks (1 results)

  • [Journal Article] Kelch-Like Protein 2 Mediates Angiotensin II-With No Lysine 3 Signaling in the Regulation of Vascular Tonus2015

    • Author(s)
      Zeniya M, Morimoto N, Takahashi D, Mori Y, Mori T, Ando F, Araki Y, Yoshizaki Y, Inoue Y, Isobe K, Nomura N, Oi K, Nishida H, Sasaki S, Sohara E, Rai T, Uchida S
    • Journal Title

      J Am Soc Nephrol

      Volume: 26 Issue: 9 Pages: 2129-2138

    • DOI

      10.1681/asn.2014070639

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters2014

    • Author(s)
      Kikuchi E, Mori T, Zeniya M, Isobe K, Ishigami-Yuasa M, Fujii S, Kagechika H, Ishihara T, Mizushima T, Sasaki S, Sohara E, Rai T, Uchida S
    • Journal Title

      J Am Soc Nephrol

      Volume: 26 Issue: 7 Pages: 1525-1536

    • DOI

      10.1681/asn.2014060560

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Aberrant Glycosylation and Localization of Polycystin-1 Cause Polycystic Kidney in an AQP11 Knockout Model.2014

    • Author(s)
      Inoue Y, Sohara E, Kobayashi K, Chiga M, Rai T, Ishibashi K, Horie S, Su X, Zhou J, Sasaki S, Uchida S.
    • Journal Title

      J Am Soc Nephrol.

      Volume: 25 Issue: 12 Pages: 2789-2799

    • DOI

      10.1681/asn.2013060614

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice2014

    • Author(s)
      Susa K, Sohara E, Rai T, Zeniya M, Mori Y, Mori T, Chiga M, Nomura N, Nishida H, Takahashi D, Isobe K, Inoue Y, Takeishi K, Takeda N, Sasaki S, Uchida S
    • Journal Title

      Hum Mol Genet

      Volume: 23 (19) Issue: 19 Pages: 5052-60

    • DOI

      10.1093/hmg/ddu217

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] WNK4 is the major WNK kinase positively regulating NCC in the mouse kidney2014

    • Author(s)
      Takahashi D, Mori T, Nomura N, Khan MZ, Araki Y, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S
    • Journal Title

      Biosci Rep

      Volume: 34 (3) Issue: 3 Pages: 195-205

    • DOI

      10.1042/bsr20140047

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of with-no-lysine kinase signaling by Kelch-like proteins2014

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

      Biol Cell

      Volume: 106(2) Issue: 2 Pages: 45-56

    • DOI

      10.1111/boc.201300069

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of blood pressure and renal electrolyte balance by Cullin-RING ligases.2014

    • Author(s)
      Uchida S.
    • Journal Title

      Curr Opin Nephrol Hypertens.

      Volume: 23 Issue: 5 Pages: 487-493

    • DOI

      10.1097/mnh.0000000000000049

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation.2013

    • Author(s)
      Chu PY, Cheng CJ, Wu YC, Fang YW, Chau T, Uchida S, Sasaki S, Yang SS, Lin SH.
    • Journal Title

      PLoS One

      Volume: 8 Issue: 9 Pages: e72969-e72969

    • DOI

      10.1371/journal.pone.0072969

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of enzyme-linked immunosorbent assays for urinary thiazide-sensitive Na-Cl cotransporter (NCC) measurement.2013

    • Author(s)
      Isobe K, Mori T, Asano T, Kawaguchi H, Nonoyama S, Kumagai N, Kamada F, Morimoto T, Hayashi M, Sohara E, Rai T, Sasaki S, Uchida S.
    • Journal Title

      Am J Physiol Renal Physiol.

      Volume: 305

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Dietary salt intake regulates WNK3-SPAK-NKCC1 phosphorylation cascade in mouse aorta through angiotensin II2013

    • Author(s)
      Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S
    • Journal Title

      Hypertension

      Volume: 62(5) Issue: 5 Pages: 872-8

    • DOI

      10.1161/hypertensionaha.113.01543

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy.2013

    • Author(s)
      Mori, T.; Kikuchi, E.; Watanabe, Y.; Fujii, S.; Ishigami-Yuasa, M.; Kagechika, H.; Sohara, E.; Rai, T.; Sasaki, S.; Uchida, S.
    • Journal Title

      Biochem. J.

      Volume: 455 Issue: 3 Pages: 339-345

    • DOI

      10.1042/bj20130597

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms2013

    • Author(s)
      Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, Sasaki S, Uchida S
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 439(1) Issue: 1 Pages: 30-4

    • DOI

      10.1016/j.bbrc.2013.08.035

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] KLHL2 interacts with and ubiquitinates WNK kinases2013

    • Author(s)
      Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 437(3) Issue: 3 Pages: 457-62

    • DOI

      10.1016/j.bbrc.2013.06.104

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Phosphorylation regulates NCC stability and transporter activity in vivo.2013

    • Author(s)
      Yang SS, Fang YW, Tseng MH, Chu PY, Yu IS, Wu HC, Lin SW, Chau T, Uchida S, Sasaki S, Lin YF, Sytwu HK, Lin SH.
    • Journal Title

      J Am Soc Nephrol.

      Volume: 24 Issue: 10 Pages: 1587-97

    • DOI

      10.1681/asn.2012070742

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Immunolocalization and translocation of aquaporin-5 water channel in sweat glands.2013

    • Author(s)
      Inoue R, Sohara E, Rai T, Satoh T, Yokozeki H, Sasaki S, Uchida S.
    • Journal Title

      J Dermatol Sci.

      Volume: 70 Issue: 1 Pages: 26-33

    • DOI

      10.1016/j.jdermsci.2013.01.013

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.2013

    • Author(s)
      Wakabayashi M
    • Journal Title

      Cell Rep.

      Volume: 28 Issue: 3 Pages: 858-868

    • DOI

      10.1016/j.celrep.2013.02.024

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Treatment with 17-allylamino-17-demethoxygeldanamycin ameliorated symptoms of Bartter syndrome type caused by mutated Bsnd in mice.2013

    • Author(s)
      Nomura N, Kamiya K, Ikeda K, Yui N, Chiga M, Sohara E, Rai T, Sasaki S, Uchida S.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 441 Issue: 3 Pages: 544-49

    • DOI

      10.1016/j.bbrc.2013.10.129

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] Impaired KLHL3-Mediated Ubiquitination of WNK4 Causes Human Hypertension.2014

    • Author(s)
      Uchida S.
    • Organizer
      The 47th Annual Meeting of American Society of Nephrology
    • Place of Presentation
      フィラデルフィア、米国
    • Year and Date
      2014-11-13 – 2014-11-16
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Clinical Significance of Urinary Thiazide-Sensitive Na-Cl Cotransporter (NCC) Measurement by Newly Development Enzyme-Linked Immunosorbent Assays.2013

    • Author(s)
      Isobe K, Mori T, Sohara E, Rai T, Sasaki S, Uchida S.
    • Organizer
      The 46th Annual meeting of American Society of Nephrology
    • Place of Presentation
      アトランタ, アメリカ合衆国
    • Related Report
      2013 Research-status Report
  • [Presentation] Impaired KLHL3-mediated ubiquitination of WNK4 activates OSR1 and SPAK kinases-NaCl cotransporter (NCC) signaling and causes hypertension.2013

    • Author(s)
      Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, Chiga M, Kikuchi E, Nomura N, Mori Y, Rai T, Sasaki S, Uchida S.
    • Organizer
      The 46th Annual meeting of American Society of Nephrology
    • Place of Presentation
      アトランタ, アメリカ合衆国
    • Related Report
      2013 Research-status Report
  • [Presentation] KLHL2 interacts with and ubiquitinates WNK kinases.2013

    • Author(s)
      Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, Sohara E, Rai T, Sasaki S, Uchida S.
    • Organizer
      The 46th Annual meeting of American Society of Nephrology
    • Place of Presentation
      アトランタ, アメリカ合衆国
    • Related Report
      2013 Research-status Report
  • [Presentation] WNK3 Regulates Blood Pressure Through the Regulation of Vascular OSR1/SPAK-NKCC1 Phosphorylation Cascade.2013

    • Author(s)
      Zeniya M, Sohara E, Kita S, Iwamoto T, Susa K, Mori T, Oi K, Chiga M, Takahashi D, Yang SS, Lin SH, Rai T, Sasaki S, Uchida S.
    • Organizer
      The 46th Annual meeting of American Society of Nephrology
    • Place of Presentation
      アトランタ, アメリカ合衆国
    • Related Report
      2013 Research-status Report
  • [Presentation] Chemical library screening for WNK signaling inhibitors by using fluorescent correlation spectroscopy.2013

    • Author(s)
      Mori T, Eriko K, Sohara E, Rai T, Sasaki S, Uchida S.
    • Organizer
      The 46th Annual meeting of American Society of Nephrology
    • Place of Presentation
      アトランタ, アメリカ合衆国
    • Related Report
      2013 Research-status Report
  • [Remarks] 東京医科歯科大学腎臓内科学

    • URL

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

    • Related Report
      2013 Research-status Report

URL: 

Published: 2014-07-25   Modified: 2019-07-29  

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