CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-κB activation
CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-κB activation
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CPUY192018 是 Keap1-Nrf2 蛋白-蛋白相互作用的有效抑制剂，通过限制氧化应激和 NF-kappa B 激活来减轻小鼠肾脏炎症
DOI：
10.1016/j.redox.2019.101266
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发表时间：
2019-09-01
期刊：
影响因子：
11.4
通讯作者：
Jiang, Zheng-Yu
中科院分区：
文献类型：
--
作者：
Lu, Meng-Chen;Zhao, Jing;Jiang, Zheng-Yu
Keap 1-Nrf 2-ARE途径调节编码解毒酶、抗氧化蛋白和抗炎蛋白的各种基因的组成型和诱导型转录，并且在防御细胞氧化应激中具有关键作用。在这项研究中，我们研究了CPUY 192018的治疗潜力，CPUY 192018是Keap 1-Nrf 2蛋白质-蛋白质相互作用（PPI）的有效小分子抑制剂，在肾脏炎症中。在人近端肾小管上皮细胞HK-2中，CPUY 192018处理显著增加Nrf 2蛋白水平和Nrf 2核转位，从而以Nrf 2依赖的方式增强Nrf 2-ARE转录能力和下游蛋白含量。在脂多糖（LPS）攻击的人HK-2细胞中，CPUY 192018通过增强Nrf 2-ARE调节的抗氧化系统表现出细胞保护作用，并通过阻碍ROS介导的NF-κ B通路的活化来减少LPS诱导的炎症反应。在LPS诱导的慢性肾脏炎症小鼠模型中，通过激活Nrf 2，CPUY 192018治疗平衡了肾脏氧化应激并抑制了炎症反应。因此，CPUY 192018的施用减少了肾损伤并改善了肾小球的病理学改变。综上所述，我们的研究表明，小分子Keap 1-Nrf 2 PPI抑制剂可以激活基于Nrf 2的细胞保护系统，保护肾脏免受炎症损伤，从而提高了Keap 1-Nrf 2 PPI抑制剂在治疗炎症性肾脏疾病中的潜在应用。
The Keap1-Nrf2-ARE pathway regulates the constitutive and inducible transcription of various genes that encode detoxification enzymes, antioxidant proteins and anti-inflammatory proteins and has pivotal roles in the defence against cellular oxidative stress. In this study, we investigated the therapeutic potential of CPUY192018, a potent small-molecule inhibitor of the Keap1-Nrf2 protein-protein interaction (PPI), in renal inflammation. In human proximal tubular epithelial HK-2 cells, CPUY192018 treatment significantly increased Nrf2 protein level and Nrf2 nuclear translocation, which enhanced Nrf2-ARE transcription capacity and the downstream protein content in a Nrf2 dependent manner. In lipopolysaccharide (LPS)-challenged human HK-2 cells, CPUY192018 exhibited cytoprotective effects by enhancing the Nrf2-ARE regulated antioxidant system and diminished the LPS-induced inflammatory response by hindering the ROS-mediated activation of the NF-kappa B pathway. In the LPS-induced mouse model of chronic renal inflammation, by activating Nrf2, CPUY192018 treatment balanced renal oxidative stress and suppressed inflammatory responses. Hence, administration of CPUY192018 reduced kidney damage and ameliorated pathological alterations of the glomerulus. Taken together, our study suggested that small-molecule Keap1-Nrf2 PPI inhibitors can activate the Nrf2-based cytoprotective system and protect the kidney from inflammatory injury, raising a potential application of Keap1-Nrf2 PPI inhibitors in the treatment of inflammatory kidney disorders.