Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease

Oxidative stress and inflammation are mediators in the development and progression of chronic kidney disease (CKD) and its complications, and they are inseparably linked as each begets and amplifies the other. CKD-associated oxidative stress is due to increased production of reactive oxygen species...

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Bibliographic Details
Published in:Kidney international 2013-06, Vol.83 (6), p.1029-1041
Main Authors: Ruiz, Stacey, Pergola, Pablo E., Zager, Richard A., Vaziri, Nosratola D.
Format: Article
Language:English
Subjects:
Acute Kidney Injury - drug therapy
Acute Kidney Injury - immunology
Acute Kidney Injury - metabolism
Animals
Anti-Infective Agents - therapeutic use
antioxidant therapy
Antioxidants - therapeutic use
cardiovascular disease
CKD progression
Disease Progression
ESRD
Humans
inflammation
Inflammation - diagnosis
Inflammation - drug therapy
Inflammation - immunology
Inflammation - metabolism
Kidney - drug effects
Kidney - immunology
Kidney - metabolism
Kidney Failure, Chronic - drug therapy
Kidney Failure, Chronic - immunology
Kidney Failure, Chronic - metabolism
NF-E2-Related Factor 2 - agonists
NF-E2-Related Factor 2 - metabolism
Oleanolic Acid - analogs & derivatives
Oleanolic Acid - therapeutic use
oxidative stress
Oxidative Stress - drug effects
Renal Insufficiency, Chronic - diagnosis
Renal Insufficiency, Chronic - drug therapy
Renal Insufficiency, Chronic - immunology
Renal Insufficiency, Chronic - metabolism
Time Factors
Treatment Outcome
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Summary:Oxidative stress and inflammation are mediators in the development and progression of chronic kidney disease (CKD) and its complications, and they are inseparably linked as each begets and amplifies the other. CKD-associated oxidative stress is due to increased production of reactive oxygen species (ROS) and diminished antioxidant capacity. The latter is largely caused by impaired activation of Nrf2, the transcription factor that regulates genes encoding antioxidant and detoxifying molecules. Protective effects of Nrf2 are evidenced by amelioration of oxidative stress, inflammation, and kidney disease in response to natural Nrf2 activators in animal models, while Nrf2 deletion amplifies these pathogenic pathways and leads to autoimmune nephritis. Given the role of impaired Nrf2 activity in CKD-induced oxidative stress and inflammation, interventions aimed at restoring Nrf2 may be effective in retarding CKD progression. Clinical trials of the potent Nrf2 activator bardoxolone methyl showed significant improvement in renal function in CKD patients with type 2 diabetes. However, due to unforeseen complications the BEACON trial, which was designed to investigate the effect of this drug on time to end-stage renal disease or cardiovascular death in patients with advanced CKD, was prematurely terminated. This article provides an overview of the role of impaired Nrf2 activity in the pathogenesis of CKD-associated oxidative stress and inflammation and the potential utility of targeting Nrf2 in the treatment of CKD.
ISSN:0085-2538
1523-1755
DOI:10.1038/ki.2012.439