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Targeting the KEAP1-NRF2 System to Prevent Kidney Disease Progression
Masahiro Nezu1, Norio Suzuki, Masayuki Yamamoto
1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
American Journal of Nephrology
|May 16, 2017
Summary
Activating the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) pathway protects kidneys from damage and oxidative stress. KEAP1 inhibitors show promise for treating kidney disease, with ongoing trials demonstrating safety and efficacy in early stages.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcription factor regulating antioxidative and detoxification genes.
- Kelch-like ECH-associated protein 1 (KEAP1) controls NRF2 stability by targeting it for degradation.
- The KEAP1-NRF2 pathway is implicated in kidney disease pathogenesis due to oxidative stress.
Purpose of the Study:
- To evaluate the therapeutic potential of targeting the KEAP1-NRF2 system for renal protection.
- To assess the efficacy and safety of KEAP1 inhibitors in preclinical and clinical settings of kidney disease.
Main Methods:
- Studies involved animal models of acute kidney injury (AKI) and clinical trials in patients with chronic kidney disease (CKD).
- Methods included genetic and pharmacological enhancement of NRF2 activity.
- Clinical trials assessed glomerular filtration rate and cardiovascular safety.
Main Results:
- Enhancing NRF2 activity in renal tubules ameliorated AKI and prevented progression to CKD by reducing oxidative stress.
- A phase-3 trial of a KEAP1 inhibitor was halted due to cardiovascular events in advanced CKD patients.
- Phase-2 trials in moderate CKD patients showed KEAP1 inhibitors improved glomerular filtration rate without safety concerns.
Conclusions:
- The KEAP1-NRF2 system represents a significant therapeutic target for kidney diseases.
- KEAP1 inhibitors demonstrate potential for treating kidney disease, particularly in earlier stages.
- Careful patient selection and monitoring are crucial for the safe application of KEAP1 inhibitors in CKD treatment.
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