Investigation of cross-talk between salt-sensitive hypertension and metabolic syndrome via WNK4

• Project/Area Number: 17K16077
• 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: TAKAHASHI Daiei 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (40759552)
• 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: 脂肪分化 / WNK4 / 3T3-L1 / メタボリックシンドローム / PPARγ / C/EBPα / WNK４ / ３T3-L1 / 肥満 / 高血圧

Outline of Final Research Achievements

In the WNK4-/- mice, PPARγ and C/EBPα, known as master regulators of adipocyte differentiation, expression levels were decreased in adipose tissues, and the mice exhibited partial resistance to high-fat diet-induced adiposity. WNK4 is induced in the early phase of 3T3-L1 adipocyte differentiation in advance of PPARγ and C/EBPα increase in preadipocytes and is expressed in mouse mature adipose tissues. It is known that preadipocytes grow into mature adipocytes via cell division called mitotic clonal expansion (MCE). We investigated whether WNK4 is important for the MCE using BrdU stain and by the evaluation of cyclin protein abundance. As a result, MCE was markedly decreased in WNK4 knock down preadipocytes. This results indicates WNK4 have an important role for MCE in preadipocytes. We have reported these results on EBioMedicine.

Academic Significance and Societal Importance of the Research Achievements

メタボリックシンドローム(metabolic syndrome、MetS)は、高血圧、インスリン抵抗性、脂質代謝異常、内臓脂肪型肥満からなる症候群である。WNK4はそのキナーゼ機能が活性化することにより、腎での塩分再吸収を促進し塩分感受性高血圧を引き起こすことが知られている。本研究によりWNK4は脂肪細胞でも発現し、前駆脂肪細胞から成熟脂肪細胞に分化するのに必要な細胞分裂に重要な働きをしていることが明らかになった。この研究結果によりメタボリックシンドロームのような病態に対し、WNK4が包括的な治療ターゲットとなりえることが明らかになった。

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] 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] WNK4 Deletion Inhibits Adipogenesis In Vitro and In Vivo (2017)
  • Author(s): Takahashi Daiei、Mori Takayasu、Sohara Eisei、Tanaka Miyako、Chiga Motoko、Inoue Yuichi、Nomura Naohiro、Zeniya Moko、Rai Tatemitsu、Uchida Shinichi
  • Organizer: The 50th Annual Meeting of American Society of Nephrology
  • Int'l Joint Research
• [Presentation] WNK4は脂肪細胞分化の制御因子である (2017)
  • Author(s): 高橋 大栄、森 崇寧、蘇原 映誠、田中 都、千賀 宗子、井上 佑一、野村 尚弘、銭谷 慕子、越智 広樹、竹田 秀、菅波 孝祥、頼 建光、内田 信一
  • Organizer: 第60回日本腎臓学会学術集会
• [Presentation] WNK4は脂肪細胞分化の制御因子である (2017)
  • Author(s): 高橋 大栄
  • Organizer: 第8回分子腎臓フォーラム
• [Remarks] 血圧制御因子WNK4が脂肪細胞の分化も制御する - メタボの病態解明に進展
  • URL: https://news.mynavi.jp/article/20170403-a193/
• [Remarks] 血圧制御因子WNK4が脂肪組織では脂肪細胞の分化を制御する
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20170330.pdf