Effect of redox modulating NRF2 activators on chronic kidney disease

Bo-hyun Choi, Kyung-Shin Kang, Mi-Kyoung Kwak, Bo-hyun Choi, Kyung-Shin Kang, Mi-Kyoung Kwak

Abstract

Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no single treatment to improve kidney function in CKD patients. Since biological markers representing oxidative stress are significantly elevated in CKD patients, oxidative stress is receiving attention as a contributing factor to CKD pathology. Nuclear factor erythroid-2 related factor 2 (NRF2) is a predominant transcription factor that regulates the expression of a wide array of genes encoding antioxidant proteins, thiol molecules and their generating enzymes, detoxifying enzymes, and stress response proteins, all of which can counteract inflammatory and oxidative damages. There is considerable experimental evidence suggesting that NRF2 signaling plays a protective role in renal injuries that are caused by various pathologic conditions. In addition, impaired NRF2 activity and consequent target gene repression have been observed in CKD animals. Therefore, a pharmacological intervention activating NRF2 signaling can be beneficial in protecting against kidney dysfunction in CKD. This review article provides an overview of the role of NRF2 in experimental CKD models and describes current findings on the renoprotective effects of naturally occurring NRF2 activators, including sulforaphane, resveratrol, curcumin, and cinnamic aldehyde. These experimental results, coupled with recent clinical experiences with a synthetic triterpenoid, bardoxolone methyl, have brought a light of hope for ameliorating CKD progression by preventing oxidative stress and maintaining cellular redox homeostasis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulation of antioxidant and detoxifying genes by the NRF2-Keap1 pathway. Under normal conditions, NRF2 is continuously degraded by the KEAP1-Cul3-proteasome axis. When Cys residues of KEAP1 protein are modified by sulfhydryl reactive chemicals, conformational KEAP1 changes lead to NRF2 liberation and transcriptional activation of an array of ARE-bearing genes, encoding detoxifying enzymes, ROS scavenging enzymes, thiol molecules, and their generating enzymes.
Figure 2
Figure 2
Factors involved in the progression of kidney dysfunction in CKD and the role of NRF2. In CKD, the alteration of mitochondrial function and the activation of ROS-generating enzymes such as NADPH oxidase and xanthine oxidase participate in aggravated oxidative stress condition in the kidney. The activation of the renin-angiotensin system is another important contributing factor. In addition, oxidative stress triggers NF-κB activation and enhances inflammatory response, which is an important pathologic component of CKD. NRF2 provides renal cells with antioxidant potential by up-regulating an array of genes and consequently attenuates the production of pro-inflammatory cytokines and adhesion molecules.

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