Departments of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea.
Department of Pharmacology, Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, 61469, South Korea.
Sci Rep. 2018 Aug 1;8(1):11546. doi: 10.1038/s41598-018-30008-5.
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.
肾小管间质纤维化是肾脏疾病的共同特征。据报道，组蛋白去乙酰化酶（HDAC）抑制剂可减轻肾纤维化进展。在这里，我们研究了新型 HDAC 抑制剂 CG200745 在单侧输尿管梗阻（UUO）小鼠模型中对肾纤维化发展的影响。为了研究 CG200745 对 UUO 肾纤维化的影响，将 C57BL/6J 雄性小鼠分为三组：对照组、UUO 组和 CG200745（30mg/kg/天）治疗的 UUO 组。CG200745 通过饮用水给药 1 周。还将人近端肾小管上皮（HK-2）细胞用 CG200745（10µM）与或不与 TGF-β（2ng/mL）处理。UUO 后 7 天，各组血浆肌酐无差异。然而，UUO 组的血浆中性粒细胞明胶酶相关脂质运载蛋白（NGAL）水平明显升高，CG200745 治疗可减轻该升高。UUO 肾脏出现明显纤维化，表现为胶原蛋白沉积和α-平滑肌肌动蛋白（α-SMA）和纤维连接蛋白表达增加。CG200745 治疗可减轻这些纤维化反应，并抑制 UUO 诱导的转化生长因子-β1（TGF-β）产生和 Smad-2/3 磷酸化。CG200745 治疗还可减轻 UUO 诱导的炎症，表现在炎症标志物的表达上。此外，CG200745 可减轻 UUO 肾脏中 p38 丝裂原活化蛋白激酶的磷酸化。在 HK-2 细胞中，TGF-β诱导α-SMA 和纤维连接蛋白的表达，CG200745 共处理可减弱其表达。这些结果表明，新型 HDAC 抑制剂 CG200745 通过抑制 UUO 小鼠模型中的肾纤维化和炎症具有肾脏保护作用。
