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
  • 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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