Inhibition of G protein-coupled receptor 68 using homoharringtonine attenuates chronic kidney disease-associated cardiac impairment

Yuya Yoshida, Kohei Fukuoka, Miyu Sakugawa, Masayuki Kurogi, Kengo Hamamura, Keika Hamasaki, Fumiaki Tsurusaki, Kurumi Sotono, Takumi Nishi, Taiki Fukuda, Taisei Kumamoto, Kosuke Oyama, Takashi Ogino, Akito Tsuruta, Kouta Mayanagi, Tomohiro Yamashita, Hiroyuki Fuchino, Nobuo Kawahara, Kayo Yoshimatsu, Hitomi KawakamiSatoru Koyanagi, Naoya Matsunaga, Shigehiro Ohdo

研究成果: ジャーナルへの寄稿学術誌査読

5 被引用数 (Scopus)

抄録

Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia, inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD.

本文言語英語
ページ(範囲)31-46
ページ数16
ジャーナルTranslational Research
269
DOI
出版ステータス出版済み - 7月 2024

!!!All Science Journal Classification (ASJC) codes

  • 公衆衛生学、環境および労働衛生
  • 生理学(医学)
  • 生化学、医学

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