Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression

被引:167
作者
Nezu, Masahiro [1 ,2 ,3 ]
Suzuki, Norio [2 ]
Yamamoto, Masayuki [1 ,3 ]
机构
[1] Tohoku Univ, Grad Sch Med, Dept Med Biochem, Sendai, Miyagi, Japan
[2] Tohoku Univ, Grad Sch Med, Div Oxygen Biol, Sendai, Miyagi, Japan
[3] Tohoku Univ, Grad Sch Med, Tohoku Med Megabank Org, Sendai, Miyagi, Japan
关键词
Oxidative stress; Acute kidney injury; Chronic kidney disease; Clinical trials; TRANSCRIPTION FACTOR NRF2; ISCHEMIA-REPERFUSION INJURY; CISPLATIN-INDUCED NEPHROTOXICITY; INDUCED DIABETIC-NEPHROPATHY; PLACEBO-CONTROLLED PHASE-3; OXIDATIVE STRESS; BARDOXOLONE METHYL; CARDIOVASCULAR EVENTS; NITROSATIVE STRESS; ANGIOTENSIN-II;
D O I
10.1159/000475890
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background: 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. Summary: 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. (C) 2017 S. Karger AG, Basel
引用
收藏
页码:473 / 483
页数:11
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