TY - JOUR
T1 - Inhibition of G protein-coupled receptor 68 using homoharringtonine attenuates chronic kidney disease-associated cardiac impairment
AU - Yoshida, Yuya
AU - Fukuoka, Kohei
AU - Sakugawa, Miyu
AU - Kurogi, Masayuki
AU - Hamamura, Kengo
AU - Hamasaki, Keika
AU - Tsurusaki, Fumiaki
AU - Sotono, Kurumi
AU - Nishi, Takumi
AU - Fukuda, Taiki
AU - Kumamoto, Taisei
AU - Oyama, Kosuke
AU - Ogino, Takashi
AU - Tsuruta, Akito
AU - Mayanagi, Kouta
AU - Yamashita, Tomohiro
AU - Fuchino, Hiroyuki
AU - Kawahara, Nobuo
AU - Yoshimatsu, Kayo
AU - Kawakami, Hitomi
AU - Koyanagi, Satoru
AU - Matsunaga, Naoya
AU - Ohdo, Shigehiro
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/7
Y1 - 2024/7
N2 - 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.
AB - 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.
KW - Cardiac inflammation
KW - Cephalotaxus harringtonia var
KW - Chronic kidney disease
KW - GPR68
KW - Homoharringtonine
KW - Nana
UR - http://www.scopus.com/inward/record.url?scp=85187380772&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85187380772&partnerID=8YFLogxK
U2 - 10.1016/j.trsl.2024.02.004
DO - 10.1016/j.trsl.2024.02.004
M3 - Article
C2 - 38401836
AN - SCOPUS:85187380772
SN - 1931-5244
VL - 269
SP - 31
EP - 46
JO - Translational Research
JF - Translational Research
ER -