2. Academic Validation
  3. Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

Inhibition of G0/G1 Switch 2 Ameliorates Renal Inflammation in Chronic Kidney Disease

  • EBioMedicine. 2016 Nov;13:262-273. doi: 10.1016/j.ebiom.2016.10.008.
Naoya Matsunaga 1,  Eriko Ikeda 2,  Keisuke Kakimoto 3,  Miyako Watanabe 3,  Naoya Shindo 4,  Akito Tsuruta 3,  Hisako Ikeyama 3,  Kengo Hamamura 2,  Kazuhiro Higashi 3,  Tomohiro Yamashita 5,  Hideaki Kondo 6,  Yuya Yoshida 3,  Masaki Matsuda 3,  Takashi Ogino 3,  Kazutaka Tokushige 3,  Kazufumi Itcho 3,  Yoko Furuichi 3,  Takaharu Nakao 3,  Kaori Yasuda 7,  Atsushi Doi 7,  Toshiaki Amamoto 8,  Hironori Aramaki 2,  Makoto Tsuda 9,  Kazuhide Inoue 5,  Akio Ojida 4,  Satoru Koyanagi 1,  Shigehiro Ohdo 10
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Molecular Biology, Daiichi University of Pharmacy, Minami-ku, Fukuoka 815-8511, Japan.
  • 3 Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
  • 4 Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
  • 5 Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • 6 Center for Sleep Medicine, Saiseikai Nagasaki Hospital, Katafuchi, Nagasaki 850-0003, Japan.
  • 7 Cell-Innovator Inc., EC building, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
  • 8 NMedical Co. Ouryokukai, Chuo-ku, Nihombashi-Kayabacho, Tokyo 103-0025, Japan.
  • 9 Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
  • 10 Department of Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: [email protected].
PMID: 27745900 DOI: 10.1016/j.ebiom.2016.10.008
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/G1 switch 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.

Keywords

Chronic renal disease; Circadian clock; G0s2; Small compound inhibitor.

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