Regulation Mechanism of blood pressure through analysis of KLHL2/3 in vivo

• Project/Area Number: 17K16076
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ZENIYA Moko 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (10760283)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 高血圧 / KLHL3 / KLHL2 / ナトリウム輸送体 / 塩分感受性

Outline of Final Research Achievements

WNK-OSR1/SPAK-NCC phosphorylation cascade is involved in salt-sensitive hypertension through regulation of renal sodium excretion and vasoconstriction. WNK kinases are mediated by KLHL2 and KLHL3, however, the detailed mechanism remained unknown. In this study, we generated KLHL2 knock-out (KO) and KLHL3 KO mice and analyzed their phenotypes. As a result, we elucidated the localization in vivo of KLHL2 and KLHL3, involvement of KLHL2 and KLHL3 in salt-sensitive hypertension, and the pathophysiological roles of KLHL2 and KLHL3 for the regulation of WNK-OSR1/SPAK-NCC cascade.
In addition, we also clarified that the WNK cascade is upregulated in salt-sensitive hypertension observed in chronic kidney disease (CKD). Proteasome inhibitor bortezomib were identified as a novel therapeutic candidate for fibrosis in CKD.

Academic Significance and Societal Importance of the Research Achievements

高血圧患者は日本に1000万人以上存在し、中でも塩分感受性高血圧は臓器障害を起こしやすく、その対策は大変重要な課題である。今回我々が一連の研究により、KLHL3及びKLHL2の生体・特に腎臓における機能を解明したことで、WNK-OSR1/SPAK-NCCカスケードの上位調節機構について、より詳細な仕組みが明らかになった。このことは、塩分感受性高血圧の今後の病態全容解明や治療法開発に向けた学術的・社会的前進であると考えている。

Research Products

• [Journal Article] Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney (2018)
  • Author(s): Nomura Naohiro、Shoda Wakana、Wang Yuanlong、Mandai Shintaro、Furusho Taisuke、Takahashi Daiei、Zeniya Moko、Sohara Eisei、Rai Tatemitsu、Uchida Shinichi
  • Journal Title: Bioscience Reports Volume: 38 Issue: 1 Pages: 20171243-1243
  • DOI: 10.1042/bsr20171243
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The proteasome inhibitor bortezomib attenuates renal fibrosis in mice via the suppression of TGF-β1 (2017)
  • Author(s): Zeniya Moko、Mori Takayasu、Yui Naofumi、Nomura Naohiro、Mandai Shintaro、Isobe Kiyoshi、Chiga Motoko、Sohara Eisei、Rai Tatemitsu、Uchida Shinichi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 13086-13086
  • DOI: 10.1038/s41598-017-13486-x
  • Peer Reviewed / Open Access
• [Journal Article] Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice. (2017)
  • Author(s): Kasagi Y, Takahashi D, Aida T, Nishida H, Nomura N, Zeniya M, Mori T, Sasaki E, Ando F, Rai T, Uchida S, Sohara E.
  • Journal Title: Biochem Biophys Res Commun. Volume: 487 Issue: 2 Pages: 368-374
  • DOI: 10.1016/j.bbrc.2017.04.068
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3. (2017)
  • Author(s): Sasaki E, Susa K, Mori T, Isobe K, Araki Y, Inoue Y, Yoshizaki Y, Ando F, Mori Y, Mandai S, Zeniya M, Takahashi D, Nomura N, Rai T, Uchida S, Sohara E.
  • Journal Title: Mol Cell Biol. Volume: 27 Issue: 7 Pages: 1-13
  • DOI: 10.1128/mcb.00508-16
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Drug-Repositioning Screening for Keap1-Nrf2 Binding Inhibitors using Fluorescence Correlation Spectroscopy (2017)
  • Author(s): Yoshizaki Yuki、Mori Takayasu、Ishigami-Yuasa Mari、Kikuchi Eriko、Takahashi Daiei、Zeniya Moko、Nomura Naohiro、Mori Yutaro、Araki Yuya、Ando Fumiaki、Mandai Shintaro、Kasagi Yuri、Arai Yohei、Sasaki Emi、Yoshida Sayaka、Kagechika Hiroyuki、Rai Tatemitsu、Uchida Shinichi、Sohara Eisei
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 3945-3945
  • DOI: 10.1038/s41598-017-04233-3
  • Peer Reviewed / Open Access
• [Journal Article] WNK4 is an Adipogenic Factor and Its Deletion Reduces Diet-Induced Obesity in Mice. (2017)
  • Author(s): Takahashi D, Mori T, Sohara E, Tanaka M, Chiga M, Inoue Y, Nomura N, Zeniya M, Ochi H, Takeda S, Suganami T, Rai T, Uchida S.
  • Journal Title: EBioMedicine Volume: 18 Pages: 118-27
  • DOI: 10.1016/j.ebiom.2017.03.011
  • Peer Reviewed / Open Access
• [Presentation] WNK1-SPAK-NCC Signaling Cascade Is Involved in Salt Sensitive Hypertension Induced by Aristolochic Acid Nephropathy (2018)
  • Author(s): Taisuke Furusho, Eisei Sohara, Shintaro Mandai, Hiroaki Kikuchi, Fumiaki Ando, Moko Zeniya, Takayasu Mori, Naohiro Nomura, Tatemitsu Rai, Shinichi Uchida.
  • Organizer: The 5１ｓｔ Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Presentation] 新規腎線維化改善薬としてのbortezomibの検討 (2017)
  • Author(s): 銭谷慕子, 森崇寧, 油井直史, 野村尚弘, 千賀宗子, 高橋大栄, 蘇原映誠, 頼建光, 内田信一
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] KLHL2 は腎臓でWNK4 蛋白の分解を行う (2017)
  • Author(s): 笠木祐里, 蘇原映誠, 相田知海, 高橋大栄, 西田秀範, 野村尚弘, 銭谷慕子, 森崇寧, 佐々木絵美, 安藤史顕, 頼建 光, 内田信一
  • Organizer: 第 60 回日本腎臓学会学術総会
• [Presentation] Generation and Analysis of KLHL2 Knockout Mice (2017)
  • Author(s): Yuri Kasagi, Daiei Takahashi, Tomomi Aida, Hidenori Nishida, Naohiro Nomura, Moko Zeniya, Takayasu Mori, Emi Sasaki, Fumiaki Ando, Tatemitsu Rai, Shinichi Uchida, Eisei Sohara.
  • Organizer: The 50yh Annual Meeting of the American Society of Nephrology
  • Int'l Joint Research
• [Remarks] 多発性骨髄腫治療薬のボルテゾミブは腎臓の線維化を抑制 する -新しい慢性腎臓病治療薬となる可能性-
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20171017_1.pdf