title: Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease.
abstract: Chronic kidney disease (CKD) is a global health problem, and novel therapies to treat CKD are urgently needed. Here, we show that inhibition of G0/G1switch 2 (G0s2) ameliorates renal inflammation in a mouse model of CKD. Renal expression of chemokine (C-C motif) ligand 2 (Ccl2) was increased in response to p65 activation in the kidneys of wild-type 5/6 nephrectomy (5/6Nx) mice. Moreover, 5/6Nx Clk/Clk mice, which carry homozygous mutations in the gene encoding circadian locomotor output cycles kaput (CLOCK), did not exhibit aggravation of apoptosis or induction of F4/80-positive cells. The renal expression of G0s2 in wild-type 5/6Nx mice was important for the transactivation of Ccl2 by p65. These pathologies were ameliorated by G0s2 knockdown. Furthermore, a novel small-molecule inhibitor of G0s2 expression was identified by high-throughput chemical screening, and the inhibitor suppressed renal inflammation in 5/6Nx mice. These findings indicated that G0s2 inhibitors may have applications in the treatment of CKD.
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Matsunaga
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Ikeda
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kakimoto
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Shindo
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Tsuruta
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Ikeyama
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hamamura
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Higashi
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Center for Sleep Medicine, Saiseikai Nagasaki Hospital, Katafuchi, Nagasaki 850-0003, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ogino
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Tokushige
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Itcho
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Furuichi
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Nakao
authors.affiliation: Cell-Innovator Inc., EC building, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Cell-Innovator Inc., EC building, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Doi
authors.affiliation: NMedical Co. Ouryokukai, Chuo-ku, Nihombashi-Kayabacho, Tokyo 103-0025, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Amamoto
authors.affiliation: Department of Molecular Biology, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Aramaki
authors.affiliation: Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Ojida
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; Department of Glocal Healthcare Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.affiliation: Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: ohdo@phar.kyushu-u.ac.jp.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
mesh_terms: D000818:Animals; D001665:Binding Sites; D056926:CLOCK Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D018797:Cell Cycle Proteins; D018932:Chemokine CCL2; C508072:G0S2 protein, mouse; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D051996:Transcription Factor RelA; D056926:CLOCK Proteins
keywords: Chronic renal disease; Circadian clock; G0s2; Small compound inhibitor