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NRF2 in kidney physiology and disease
Corry D Bondi1, Hannah L Hartman1, Roderick J Tan1
1Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Physiological Reports
|February 28, 2024
Summary
The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) protects kidneys from damage. However, its role in proteinuric kidney diseases is complex and requires further investigation.
Area of Science:
- Nephrology
- Molecular Biology
- Cellular Stress Response
Background:
- Nuclear factor erythroid 2-related factor 2 (NRF2) regulates cytoprotective genes against oxidative stress and inflammation.
- NRF2 is present in the kidney and influences salt/water balance.
- Animal models suggest NRF2 protects against tubulointerstitial damage and kidney disease progression.
Purpose of the Study:
- To review the dual role of NRF2 in kidney biology, encompassing both protective and potentially detrimental effects.
- To clarify the controversies surrounding NRF2 targeting in proteinuric kidney diseases.
- To summarize current data on the therapeutic potential and risks of modulating NRF2 activity in kidney conditions.
Main Methods:
- Literature review of existing studies on NRF2 in kidney physiology and pathology.
- Analysis of data from animal models and human clinical trials involving NRF2 modulators.
- Synthesis of evidence regarding NRF2's impact on various kidney diseases, including diabetic kidney disease and Alport syndrome.
Main Results:
- NRF2 activation shows protective effects in some kidney injuries, reducing fibrosis and atrophy.
- The NRF2 inducer bardoxolone methyl (CDDO-Me) improved glomerular filtration rate in humans but did not slow disease progression in diabetic kidney disease or Alport syndrome.
- Bardoxolone methyl was linked to adverse effects like increased proteinuria, fluid retention, and hypertension in human studies, with conflicting results in animal models.
Conclusions:
- The role of NRF2 in proteinuric glomerular diseases remains controversial and complex.
- Targeting NRF2 presents both potential benefits for kidney protection and significant risks, necessitating careful consideration.
- Further research is essential to fully elucidate the multifaceted effects of NRF2 in kidney health and disease.
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