Mechanisms of vascular tonus regulation by WNK signal

• Project/Area Number: 15H06183
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• 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): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: WNKシグナル / KLHL2 / 高血圧

Outline of Final Research Achievements

Normally, the KLHL3/CUL3 ubiquitin ligase complex degrades WNKs. In PHAII, the loss of interaction between KLHL3 and WNK4 increases levels of WNKs because of impaired ubiquitination, leading to abnormal over-activation of the WNK-OSR1/SPAK-NCC cascade in the kidney's distal convoluted tubules (DCT). KLHL2, which is highly homologous to KLHL3, was reported to ubiquitinate and degrade WNKs in vitro. Mutations in KLHL2 have not been reported in patients with PHAII, suggesting that KLHL2 plays a different physiological role than that played by KLHL3 in the kidney. To investigate the physiological roles of KLHL2 in the kidney, we generated KLHL2-/- mice. KLHL2 was predominantly expressed in the medulla compared with the cortex. Accordingly, medullary WNK4 protein levels were significantly increased in the kidneys of KLHL2-/- mice. KLHL2 is indeed a physiological regulator of WNK4 in vivo; however, its function might be different from that of KLHL3 because KLHL2 mainly localized in medulla.

Research Products

• [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] 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
• [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
• [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、賴建光、内田信一
  • Organizer: 第60回日本腎臓学会学術総会
  • Place of Presentation: 仙台国際センター・宮城県・仙台市
  • Year and Date: 2017-05-26