Elucidation of regulatory mechanism of WNK signal by protein degradation system

2018 Fiscal Year Annual Research Report

• Project/Area Number: 16H05314
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 蘇原 映誠 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (90510355)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: WNKキナーゼ / 塩分感受性 / メトホルミン / 骨格筋 / 偽性低アルドステロン症２型 / PKA / AMPK

Outline of Annual Research Achievements

偽性低アルドステロン症II型(PHAII)という遺伝性高血圧性疾患の原因遺伝子として報告されたWNKキナーゼは、腎臓において塩分出納の主たる制御機構の中心分子となり、電解質や血圧を生理的に調節していることを我々は発見しており、本研究課題では、PHAIIの病態解明だけでなく、血管、脂肪分化、筋組織分化などの全身臓器における機能を明らかにした。これらは、水電解質を高血圧や肥満などのメタボリックシンドロームや筋萎縮(サルコペニア)などの一般疾患につなげるという意味で重要な研究と考えられた。
具体的には、PHAⅡではKLHL3の発現量低下が起こることを、病態モデルノックインマウスを作成し証明した。(Clin Exp Nephrol. 2018 )。また、糖尿病治療薬であるメトホルミンが、腎遠位尿細管のNa-Cl共輸送体(NCC)のリン酸化を抑制し塩分排泄を増加させることを明らかにした(Metabolism. 2018)。血圧制御因子WNK1キナーゼが,骨格筋においてはFOXO4の転写活性を調節し骨格筋肥大を制御することを発見した。このWNK1-FOXO4シグナルの機能低下がCKDによるサルコペニアの一機序である可能性も示した(Sci Rep. 2018)。
さらにProtein Kinase A (PKA) と PKAのアンカータンパクであるAKAPsとの結合を阻害する低分子化合物FMP-API-1は、腎臓集合管のAQP2水チャネルを強力に活性化した(Nat Commun. 2018)。CKDによって蓄積される尿毒素などが腎臓や心臓、骨格筋などにおいてAMPKの機能低下をもたらし、さらなるエネルギー状態不良を生み出すという負のサイクルを解明し、AMPKのエネルギーセンサー機能を介さない直接活性化薬などがCKDの新規治療薬になる可能性を明らかにした(Kidney Int. 2019)。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Genotype-Clinical Correlations in Polycystic Kidney Disease with No Apparent Family History (2019)
  • Author(s): Sekine Akinari、Fujimaru Takuya、Hoshino Junichi、Suwabe Tatsuya、Oguro Masahiko、Mizuno Hiroki、Kawada Masahiro、Sumida Keiichi、Hiramatsu Rikako、Chiga Motoko、Kikuchi Hiroaki、Ando Fumiaki、Mori Takayasu、Sohara Eisei、Uchida Shinichi、Sawa Naoki、Takaichi Kenmei、Ubara Yoshifumi
  • Journal Title: American Journal of Nephrology Volume: 49 Pages: 233～240
  • DOI: 10.1159/000497444
  • Peer Reviewed
• [Journal Article] Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease (2019)
  • Author(s): Kikuchi Hiroaki、Sasaki Emi、Nomura Naohiro、Mori Takayasu、Minamishima Yoji Andrew、Yoshizaki Yuki、Takahashi Naohiro、Furusho Taisuke、Arai Yohei、Mandai Shintaro、Yamashita Takahiro、Ando Fumiaki、Maejima Yasuhiro、Isobe Kiyoshi、Okado Tomokazu、Rai Tatemitsu、Uchida Shinichi、Sohara Eisei
  • Journal Title: Kidney International Volume: 95 Pages: 123～137
  • DOI: 10.1016/j.kint.2018.08.030
  • Peer Reviewed
• [Journal Article] WNK1 regulates skeletal muscle cell hypertrophy by modulating the nuclear localization and transcriptional activity of FOXO4 (2018)
  • Author(s): Mandai Shintaro、Mori Takayasu、Nomura Naohiro、Furusho Taisuke、Arai Yohei、Kikuchi Hiroaki、Sasaki Emi、Sohara Eisei、Rai Tatemitsu、Uchida Shinichi
  • Journal Title: Scientific Reports Volume: 8 Pages: 9101
  • DOI: 10.1038/s41598-018-27414-0
  • Peer Reviewed / Open Access
• [Journal Article] Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo (2018)
  • Author(s): Yoshida Sayaka、Araki Yuya、Mori Takayasu、Sasaki Emi、Kasagi Yuri、Isobe Kiyoshi、Susa Koichiro、Inoue Yuichi、Bomont Pascale、Okado Tomokazu、Rai Tatemitsu、Uchida Shinichi、Sohara Eisei
  • Journal Title: Clinical and Experimental Nephrology Volume: 22 Pages: 1251～1257
  • DOI: 10.1007/s10157-018-1593-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] AKAPs-PKA disruptors increase AQP2 activity independently of vasopressin in a model of nephrogenic diabetes insipidus (2018)
  • Author(s): Ando Fumiaki、Mori Shuichi、Yui Naofumi、Morimoto Tetsuji、Nomura Naohiro、Sohara Eisei、Rai Tatemitsu、Sasaki Sei、Kondo Yoshiaki、Kagechika Hiroyuki、Uchida Shinichi
  • Journal Title: Nature Communications Volume: 9 Pages: 1411
  • DOI: 10.1038/s41467-018-03771-2
  • Peer Reviewed / Open Access
• [Journal Article] Kidney enlargement and multiple liver cyst formation implicate mutations in PKD1/2 in adult sporadic polycystic kidney disease (2018)
  • Author(s): Fujimaru T.、Mori T.、Sekine A.、Mandai S.、Chiga M.、Kikuchi H.、Ando F.、Mori Y.、Nomura N.、Iimori S.、Naito S.、Okado T.、Rai T.、Hoshino J.、Ubara Y.、Uchida S.、Sohara E.
  • Journal Title: Clinical Genetics Volume: 94 Pages: 125～131
  • DOI: 10.1111/cge.13249
  • Peer Reviewed
• [Journal Article] Metformin increases urinary sodium excretion by reducing phosphorylation of the sodium-chloride cotransporter (2018)
  • Author(s): Hashimoto Hiroko、Nomura Naohiro、Shoda Wakana、Isobe Kiyoshi、Kikuchi Hiroaki、Yamamoto Kouhei、Fujimaru Takuya、Ando Fumiaki、Mori Takayasu、Okado Tomokazu、Rai Tatemitsu、Uchida Shinichi、Sohara Eisei
  • Journal Title: Metabolism Volume: 85 Pages: 23～31
  • DOI: 10.1016/j.metabol.2018.02.009
  • Peer Reviewed
• [Presentation] 多発性嚢胞腎診療の新しい展望~ゲノムから薬剤治療まで~. (2018)
  • Author(s): 蘇原 映誠
  • Organizer: 第 48 回日本腎臓学会東部学術大会
  • Invited
• [Presentation] WNK シグナルが明らかにした塩分感受性高血圧のメカニズム. (2018)
  • Author(s): 蘇原 映誠
  • Organizer: 第 54 回高血圧関連疾患モデル学会学術総会
  • Invited
• [Presentation] ゲノムから解くADPKD: 嚢胞性腎疾患の網羅的遺伝子解析システムの開発と応用 (2018)
  • Author(s): 蘇原 映誠, 森 崇寧, 藤丸 拓也, 内田 信一.
  • Organizer: 第 61 回日本腎臓学会学術総会.
  • Invited
• [Presentation] AKAPs-PKA Disruptors Robustly Increase AQP2 Activity Independently of Vasopressin. (2018)
  • Author(s): Ando F, Yui N, Nomura N, Sohara E, Rai T, Sasaki S, Uchida S.
  • Organizer: ASN Kidney Week 2018.
  • Int'l Joint Research
• [Presentation] WNK1 suppresses LPS-induced cytokine production in macrophage (2018)
  • Author(s): Arai Y, Sohara E, Asano K, Tanaka M, Nomura N, Rai T, Uchida S.
  • Organizer: ISN Frontiers Meetings 2018.
  • Int'l Joint Research
• [Presentation] Genomic Background of Adults with Suspected Ciliopathy on Renal Biopsy. (2018)
  • Author(s): Fujimaru T, Mori T, Mandai S, Chiga M, Kikuchi H, Ando F, Mori Y, Susa K, Isobe K, Iimori S, Nomura N, Naito S, Okado T, Rai T, Nagatsuji K, Nagahama K, Mishima E, Mochizuki T, Sekine A, Hoshino J, Ubara Y, Uchida S, Sohara E.
  • Organizer: ASN Kidney Week 2018.
  • Int'l Joint Research
• [Presentation] WNK1-SPAK-NCC signaling cascade is involved in salt sensitive hypertension induced by aristolochic acid nephropathy. (2018)
  • Author(s): Furusho T, Sohara E, Mandai S, Kikuchi H, Ando F, Zeniya M, Mori T, Nomura N, Rai T, Uchida S.
  • Organizer: ASN Kidney Week 2018.
  • Int'l Joint Research
• [Presentation] Metformin has natriuretic effects through reduction of the sodium-chrolide cotransporter phosphorylation. (2018)
  • Author(s): Hashimoto H, Nomura N, Shoda W, Isobe K, Kikuchi H, Yamamoto K, Fujimaru T, Ando F, Mori T, Okado T, Rai T, Uchida S, Sohara E.
  • Organizer: ASN Kidney Week 2018.
  • Int'l Joint Research
• [Presentation] Generation and Analysis of KLHL2 Knockout Mice. (2018)
  • 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.
  • Organizer: ISN Frontiers Meetings 2018.
  • Int'l Joint Research
• [Presentation] Amelioration of Renal Fibrosis and Tubulointerstitial Damage in Fat-1 Transgenic CKD Mice by Compensation of Decreased Omega-3 Fatty Acids in the Kidney. (2018)
  • Author(s): Takahashi N, Kikuchi H, Ishihara T, Arita M, Furusho T, Ando F, Mori T, Isobe K, Susa K, Nomura N, Rai T, Uchida S, Sohara E
  • Organizer: ASN Kidney Week 2018.
  • Int'l Joint Research
• [Presentation] Decreased protein level of KLHL3 is involved in PHAII caused by CUL3 mutation. (2018)
  • Author(s): Yoshida S, Araki Y, Mori T, Sasaki E, Kasagi Y, Isobe K, Susa K, Inoue Y, Rai T, Uchida S，Sohara E.
  • Organizer: ISN Frontiers Meetings 2018
  • Int'l Joint Research