Histone deacetylase inhibitor, CG200745 attenuates renal fibrosis in obstructive kidney disease

  • Sci Rep. 2018 Aug 1;8(1):11546. doi: 10.1038/s41598-018-30008-5.
Hong Sang Choi  1 ,  Ji Hong Song  1 ,  In Jin Kim  1 ,  Soo Yeon Joo  1 ,  Gwang Hyeon Eom  2 ,  Inkyeom Kim  3 ,  Hyunju Cha  4 ,  Joong Myung Cho  4 ,  Seong Kwon Ma  1 ,  Soo Wan Kim  5 ,  Eun Hui Bae  6
Affiliations
  • 1. Departments of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea.
  • 2. Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, 61469, South Korea.
  • 3. Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, 41944, South Korea.
  • 4. CrystalGenomics, Inc., 5 F, Bldg A, Korea Bio Park, Seongnam, 13488, Korea.
  • 5. Departments of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea. [email protected].
  • 6. Departments of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea. [email protected].
PMID: 30068917 DOI: 10.1038/s41598-018-30008-5
Abstract

Tubulointerstitial fibrosis is a common feature of kidney disease. Histone deacetylase (HDAC) inhibitors have been reported to attenuate renal fibrosis progression. Here, we investigated the effect of CG200745, a novel HDAC Inhibitor, on renal fibrosis development in a mouse model of unilateral ureteral obstruction (UUO). To examine the effects of CG200745 on renal fibrosis in UUO, C57BL/6 J male mice were divided into three groups: control, UUO, and CG200745 (30 mg/kg/day)-treated UUO groups. CG 200745 was administered through drinking water for 1 week. Human proximal tubular epithelial (HK-2) cells were also treated with CG200745 (10 µM) with or without TGF-β (2 ng/mL). Seven days after UUO, plasma creatinine did not differ among the groups. However, plasma neutrophil gelatinase-associated lipocalin (NGAL) levels were markedly increased in the UUO group, which were attenuated by CG200745 treatment. UUO kidneys developed marked fibrosis as indicated by Collagen deposition and increased α-smooth muscle actin (SMA) and fibronectin expression. CG200745 treatment attenuated these fibrotic responses and suppressed UUO-induced production of transforming growth factor-beta1 (TGF-β) and phosphorylation of Smad-2/3. CG200745 treatment also attenuated UUO-induced inflammation as indicated by the expression of inflammatory markers. Furthermore, CG200745 attenuated phosphorylation of p38 mitogen-activated protein kinase in UUO kidneys. In HK-2 cells, TGF-β induced the expression of α-SMA and fibronectin, which were attenuated by CG200745 cotreatment. These results demonstrate that CG200745, a novel HDAC Inhibitor, has a renoprotective effect by suppressing renal fibrosis and inflammation in a UUO mouse model.

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