Nezu Masahiro, Suzuki Norio, Yamamoto Masayuki
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Am J Nephrol. 2017;45(6):473-483. doi: 10.1159/000475890. Epub 2017 May 13.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor for the antioxidative stress response and it activates a variety of cytoprotective genes related to redox and detoxification. NRF2 activity is regulated by the oxidative-stress sensor molecule Kelch-like ECH-associated protein 1 (KEAP1) that induces proteasomal degradation of NRF2 through ubiquitinating NRF2 under unstressed conditions. Because oxidative stress is a major pathogenic and aggravating factor for kidney diseases, the KEAP1-NRF2 system has been proposed to be a therapeutic target for renal protection.
Oxidative-stress molecules, such as reactive oxygen species, accumulate in the kidneys of animal models for acute kidney injury (AKI), in which NRF2 is transiently and slightly activated. Genetic or pharmacological enhancement of NRF2 activity in the renal tubules significantly ameliorates damage related to AKI and prevents AKI progression to chronic kidney disease (CKD) by reducing oxidative stress. These beneficial effects of NRF2 activation highlight the KEAP1-NRF2 system as an important target for kidney disease treatment. However, a phase-3 clinical trial of a KEAP1 inhibitor for patients with stage 4 CKD and type-2 diabetes mellitus (T2DM) was terminated due to the occurrence of cardiovascular events. Because recent basic studies have accumulated positive effects of KEAP1 inhibitors in moderate stages of CKD, phase-2 trials have been restarted. The data from the ongoing projects demonstrate that a KEAP1 inhibitor improves the glomerular filtration rate in patients with stage 3 CKD and T2DM without safety concerns. Key Message: The KEAP1-NRF2 system is one of the most promising therapeutic targets for kidney disease, and KEAP1 inhibitors could be part of critical therapies for kidney disease.
核因子红细胞2相关因子2（NRF2）是抗氧化应激反应的关键转录因子，它可激活多种与氧化还原和解毒相关的细胞保护基因。NRF2的活性受氧化应激传感器分子 Kelch样ECH相关蛋白1（KEAP1）的调节，在无应激条件下，KEAP1通过泛素化NRF2诱导其蛋白酶体降解。由于氧化应激是肾脏疾病的主要致病和加重因素，KEAP1-NRF2系统已被提出作为肾脏保护的治疗靶点。
氧化应激分子，如活性氧，在急性肾损伤（AKI）动物模型的肾脏中积累，其中NRF2被短暂且轻微激活。肾小管中NRF2活性的基因或药理学增强可显著改善与AKI相关的损伤，并通过降低氧化应激防止AKI进展为慢性肾脏病（CKD）。NRF2激活的这些有益作用突出了KEAP1-NRF2系统作为肾脏疾病治疗的重要靶点。然而，一项针对4期CKD和2型糖尿病（T2DM）患者的KEAP1抑制剂3期临床试验因心血管事件的发生而终止。由于最近的基础研究积累了KEAP1抑制剂在CKD中度阶段的积极作用，2期试验已重新启动。正在进行的项目数据表明，KEAP1抑制剂可提高3期CKD和T2DM患者的肾小球滤过率，且无安全性问题。关键信息：KEAP1-NRF2系统是肾脏疾病最有前景的治疗靶点之一，KEAP1抑制剂可能是肾脏疾病关键治疗方法的一部分。
