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

Abstract

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.

• Authors: Stacey Ruiz, Pablo E Pergola, Richard A Zager, Nosratola D Vaziri
• Journal: Kidney international (Kidney Int) Vol. 83 Issue 6 Pg. 1029-41 (Jun 2013) ISSN: 1523-1755 [Electronic] United States
• PMID: 23325084 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)

Chemical References

• Anti-Infective Agents
• Antioxidants
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Oleanolic Acid
• bardoxolone methyl

Topics

• Acute Kidney Injury (drug therapy, immunology, metabolism)
• Animals
• Anti-Infective Agents (therapeutic use)
• Antioxidants (therapeutic use)
• Disease Progression
• Humans
• Inflammation (diagnosis, drug therapy, immunology, metabolism)
• Kidney (drug effects, immunology, metabolism)
• Kidney Failure, Chronic (drug therapy, immunology, metabolism)
• NF-E2-Related Factor 2 (agonists, metabolism)
• Oleanolic Acid (analogs & derivatives, therapeutic use)
• Oxidative Stress (drug effects)
• Renal Insufficiency, Chronic (diagnosis, drug therapy, immunology, metabolism)
• Time Factors
• Treatment Outcome