Elucidation of the Mechanisms of Muscle-Renal Linkage and Establishment of Novel Therapeutic Strategies through Analysis of R3hdml

• Project/Area Number: 19K16942
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Chiba University
• Principal Investigator: Ishikawa Takahiro 千葉大学, 大学院医学研究院, 特任助教 (00749426)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 筋腎連関 / 糖尿病性腎症 / サルコペニア

Outline of Research at the Start

超高齢社会を迎えた我が国では、慢性腎臓病（CKD）やサルコペニアの増加が問題となっている。両者はしばしば合併し「筋腎連関」という共通のメカニズムの存在が示唆されるものの、その機序はこれまで不明であった。
我々はこれまでに新規遺伝子であるR3hdmlの解析を行い、R3hdmlがCKDやサルコペニアに関連する因子であるという結果を得てきた。本研究はR3hdmlを通して「筋腎連関」の病態メカニズムを解明し、CKD/サルコペニアの新たな治療戦略を確立する。

Outline of Final Research Achievements

This study aims to elucidate the pathogenesis of CKD and sarcopenia through the analysis of R3hdml. In mice overexpressing R3hdml, the increase in urinary protein in the diabetic state was suppressed.Expression of R3hdml increases during skeletal muscle development and differentiation in mice. Body weight and skeletal muscle mass of R3hdml knockout (KO) mice were lower compared to control mice. Expression of R3hdml increased during muscle regeneration in response to cardiotoxin (CTX)-induced muscle injury. Recovery of handgrip strength after CTX injection was significantly impaired in R3hdml KO mice, which is rescued by R3hdml.These results indicate that R3hdml is an inhibitory factor against CKD and sarcopenia.

Academic Significance and Societal Importance of the Research Achievements

今回の結果は、R3hdmlが糖尿病性腎症を始めとするCKDやサルコペニアの病態に深く関与することを示すものである。またR3hdmmlを過剰発現させることで、糖尿病性腎症やサルコペニアの状態を軽減させた。これはR3hdmlが、両者の病態において保護的な役割を果たす因子であることを示している。今後更にR3hdmlの解明することは、将来的なR3hdmlを用いた「筋腎連関」の機序解明およびCKDやサルコペニアに対する新規治療法の確立に寄与するものと期待される。

Research Products

• [Journal Article] Low dose red yeast rice with monacolin K lowers LDL cholesterol and blood pressure in Japanese with mild dyslipidemia: A multicenter, randomized trial (2021)
  • Author(s): Takuya Minamizuka ； Masaya Koshizaka ； Mayumi Shoji ； Masaya Yamaga ； Aiko Hayashi ； Kana Ide ； Shintaro Ide ； Takumi Kitamoto ； Kenichi Sakamoto ； Akiko Hattori ； Takahiro Ishikawa ； Junji Kobayashi ； Yoshiro Maezawa ； Kazuki Kobayashi ； Minoru Takemoto ； Masaru Inagaki ； Akira Endo ； Koutaro Yokote
  • Journal Title: Asia Pacific Journal of Clinical Nutrition Volume: 3 Pages: 424-435
  • Peer Reviewed
• [Journal Article] A novel podocyte protein, R3h domain containing-like, inhibits TGF-β-induced p38 MAPK and regulates the structure of podocytes and glomerular basement membrane (2021)
  • Author(s): Ishikawa Takahiro、Takemoto Minoru、Akimoto Yoshihiro、Takada-Watanabe Aki、Yan Kunimasa、Sakamoto Kenichi、Maezawa Yoshiro、Suguro Miyuki、He Liqun、Tryggvason Karl、Betsholtz Christer、Yokote Koutaro
  • Journal Title: Journal of Molecular Medicine Volume: 6 Issue: 6 Pages: 859-876
  • DOI: 10.1007/s00109-021-02050-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] R3hdml regulates satellite cell proliferation and differentiation (2019)
  • Author(s): Sakamoto Kenichi、Furuichi Yasuro、Yamamoto Masashi、Takahashi Megumi、Akimoto Yoshihiro、Ishikawa Takahiro、Shimizu Takahiko、Fujimoto Masanori、Takada‐Watanabe Aki、Hayashi Aiko、Mita Yoshitaka、Manabe Yasuko、Fujii Nobuharu L、Ishibashi Ryoichi、Maezawa Yoshiro、Betsholtz Christer、Yokote Koutaro、Takemoto Minoru
  • Journal Title: EMBO reports Volume: 20 Issue: 11 Pages: 1-12
  • DOI: 10.15252/embr.201947957
  • Peer Reviewed / Open Access / Int'l Joint Research