PowerPoint Slides for: Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression
Nezu M.
Suzuki N.
Yamamoto M.
10.6084/m9.figshare.5017160.v1
https://karger.figshare.com/articles/figure/PowerPoint_Slides_for_Targeting_the_KEAP1-NRF2_System_to_Prevent_Kidney_Disease_Progression/5017160
<p><b><i>Background:</i></b> 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. <b><i>Summary:</i></b> 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. <b><i>Key Message:</i></b> 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.</p>
2017-05-18 14:04:36
Oxidative stress
Acute kidney injury
Chronic kidney disease
Clinical trials