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Aberrant post-translational modification in diabetic nephropathy

Research Project

Project/Area Number 17K16097
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Kidney internal medicine
Research InstitutionTeikyo University

Principal Investigator

Ishizawa Kenichi  帝京大学, 医学部, 助手 (10772684)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords糖尿病性腎症 / KLHL3 / リン酸化 / 脱リン酸化 / 糖尿病 / 高血圧
Outline of Final Research Achievements

In this study, we focused on the post-translational modification of ubiquitin ligase component Kelch-like 3 (KLHL3), a novel effector of angiotensin II, and analyzed its association with diabetic nephropathy. Phosphorylation of KLHL3 was increased in the kidney of db / db mice. Renal PKC was also increased,and PKC inhibitor suppressed KLHL3 phosphorylation in vitro and in vivo. We also found that an SGLT2 inhibitor ipragliflozin ameliorated the dysregulation of KLHL3. Moreover, in an effort to dissect the mechanisms that regulate KLHL3 phosphorylation, we found that Ser/Thr phosphatase calcineurin dephosphorylates KLHL3.

Academic Significance and Societal Importance of the Research Achievements

本研究はKLHL3のリン酸化の病的意義を解明を目指すものであるが、糖尿病性腎症におけるKLHL3のリン酸化異常を突き止めたことで、病態の分子基盤の一部が解明されることとなり、臨床的有用性が高い。
また、CalcineurinがKLHL3-S433を脱リン酸化することを見出したが、Calcineurin阻害薬(CNI)は免疫抑制薬として臨床で頻用されている。CalcineurinがKLHL3の脱リン酸化酵素として働くことは重要な結果であるが、CNIによる高血圧の病態の一部を解明したことは、臨床的にも重要と考えられる。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (4 results)

All 2019 2018 2017

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (2 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Electrolyte transport in the renal collecting duct and its regulation by the renin–angiotensin–aldosterone system2019

    • Author(s)
      Yamazaki Osamu、Ishizawa Kenichi、Hirohama Daigoro、Fujita Toshiro、Shibata Shigeru
    • Journal Title

      Clinical Science

      Volume: 133 Issue: 1 Pages: 75

    • DOI

      10.1042/cs20180194

    • URL

      https://localhost/en/publications/72a7945b-2319-4bbc-a887-0b81e2abd459

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ULK1 Phosphorylates and Regulates Mineralocorticoid Receptor2018

    • Author(s)
      Shibata Shigeru、Ishizawa Kenichi、Wang Qin、Xu Ning、Fujita Toshiro、Uchida Shunya、Lifton Richard P.
    • Journal Title

      Cell Reports

      Volume: 24 Issue: 3 Pages: 569-576

    • DOI

      10.1016/j.celrep.2018.06.072

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Dysregulation of the ubiquitin ligase component kelch-like 3 causes Na-Cl cotransporter activation and salt retention in obese diabetic mice2018

    • Author(s)
      Kenichi Ishizawa
    • Organizer
      Annual meetings of American Society of Nephrology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Pathogenic role of ubiquitin ligase KLHL3 in diabetic nephropathy2017

    • Author(s)
      Kenichi Ishizawa
    • Organizer
      AHA Conucil of Hypertension 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

URL: 

Published: 2017-04-28   Modified: 2020-03-30  

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