The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of oxidative stress defence in the human body. As Nrf2 regulates the expression of a large battery of cytoprotective genes, it plays a crucial role in the prevention of degenerative disease in multiple organs. Thus it has been the focus of research as a pharmacological target that could be used for prevention and treatment of chronic diseases such as multiple sclerosis, chronic kidney disease or cardiovascular diseases. The present review summarizes promising findings from basic research and shows which Nrf2-targeting therapies are currently being investigated in clinical trials and which agents have already entered clinical practice.

INTRODUCTION

The human body is equipped with a broad set of antioxidant defence mechanisms which protect cells from intrinsic and extrinsic cellular stress. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) (gene name NFE2L2; HGNC:7782) is a major regulator of the adaptive response to oxidative stress and orchestrates the expression of a large battery of cytoprotective genes such as antioxidants, phase II enzymes and membrane transporters. It is a cap'n'collar transcription factor with leucine–zipper elements which are necessary for DNA binding during transcription. Target genes contain an ARE (antioxidant-response element) in their promoter, which is a specific Nrf2-binding site by which Nrf2 induces gene transcription.

The distinct steps of Nrf2 signalling have been widely established in the last few years (reviewed in detail in [14]) (Figure 1). Under basal unstressed conditions, Nrf2 is constitutively expressed and degraded directly by its cytoplasmic antagonist Keap1 (Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1) (also known as iNrf2; gene name KEAP1; HGNC: 23177). Keap1 is an adaptor protein that facilitates Nrf2 binding to the E3-ubiquitin ligase complex Cul3 (cullin 3) and Rbx1 (RING box protein 1). Potentially toxic reactive molecules such as ROS (reactive oxygen species) modify cysteine residues of Keap1 and thereby prevent Nrf2 degradation in the proteasome [5]. Recently, new non-canonical ways of Nrf2 activation have been described, one involving p62/SQSTM1 (Sequestome-1), a regulator of autophagy and xenophagy. This factor binds to Keap1 and induces its autophagic degradation, which subsequently leads to Nrf2 stabilization and translocation to the nucleus [6,7].

Overview of the Nrf2/ARE signalling pathway

Figure 1
Overview of the Nrf2/ARE signalling pathway

Under basal conditions, Nrf2 is ubiquitinated by the Keap1–Cul3–Rbx complex and degraded in the proteasome (A, blue area). GSK3 is able to phosphorylate Nrf2 to induce its β-TrCP/Cul1-dependent ubiquitination and proteasomal degradation. In addition, GSK3 suppresses Nrf2 transactivation by facilitating its nuclear export via Fyn activation (B, purple area). In the case of oxidative stress or inflammation, the Keap1 dimer is dissolved from Cul3, and Nrf2 translocates to the nucleus, where it binds to ARE with small Maf proteins (sMaf), which induces the transcription of target genes (C, red area). Direct phosphorylation by kinases also allows translocation of Nrf2 to the nucleus (D, orange area). During autophagy and xenophagy, p62/SQSTM1-facilitated Keap1 degradation is suggested to be a non-canonical mechanism of Nrf2 activation (E, green area). NQO1, NAD(P)H dehydrogenase quinone 1; TNF-α, tumour necrosis factor α; Ub, ubiquitin; UGT, UDP-glucuronosyltransferase.

Figure 1
Overview of the Nrf2/ARE signalling pathway

Under basal conditions, Nrf2 is ubiquitinated by the Keap1–Cul3–Rbx complex and degraded in the proteasome (A, blue area). GSK3 is able to phosphorylate Nrf2 to induce its β-TrCP/Cul1-dependent ubiquitination and proteasomal degradation. In addition, GSK3 suppresses Nrf2 transactivation by facilitating its nuclear export via Fyn activation (B, purple area). In the case of oxidative stress or inflammation, the Keap1 dimer is dissolved from Cul3, and Nrf2 translocates to the nucleus, where it binds to ARE with small Maf proteins (sMaf), which induces the transcription of target genes (C, red area). Direct phosphorylation by kinases also allows translocation of Nrf2 to the nucleus (D, orange area). During autophagy and xenophagy, p62/SQSTM1-facilitated Keap1 degradation is suggested to be a non-canonical mechanism of Nrf2 activation (E, green area). NQO1, NAD(P)H dehydrogenase quinone 1; TNF-α, tumour necrosis factor α; Ub, ubiquitin; UGT, UDP-glucuronosyltransferase.

In addition to Keap1-dependent Nrf2 degradation, Nrf2 can be phosphorylated by GSK3β (glycogen synthase kinase 3β) which leads to β-TrCP (β-transducin repeat-containing protein) binding and Cul1-dependent ubiquitination and degradation of Nrf2 [8]. Moreover, GSK3β directly phosphorylates the kinase Fyn, leading to its activation and nuclear translocation. In the nucleus, Fyn phosphorylates Nrf2 and suppresses Nrf2 transactivation by facilitating nuclear export of Nrf2 [9]. Thus the GSK3β pathway may serve as a mechanism to deactivate Nrf2 post-induction.

An unexpected finding was that certain growth factors and cytokines are able to activate Nrf2. Our group was able to show that stimulation with VEGF (vascular endothelial growth factor) activates Nrf2 without any ROS involvement [10]. This process stabilizes Nrf2, which recruits co-factors such as small Maf proteinss and translocates to the nucleus, where it binds to the ARE sequence as a heterodimer. This induces the transcription of the according target gene. A great array of target genes, such as HO-1 (haem oxygenase-1), NQO1 [NAD(P)H dehydrogenase quinone 1] or GST has already been substantiated, with new genes constantly being discovered (Table 1).

Table 1
A selection of Nrf2 target genes

An elaborate collection of well-established target genes can be found elsewhere [93,94].

TargetDescriptionReference
Antioxidants 
 TXN Thioredoxin [95
 GSR Glutathione reductase [96
 FT Ferritin [97
Enzymes 
 NQO1 NAD(P)H dehydrogenase quinone 1 [98
 HO-1 Haem oxygenase 1 [99
 SOD Superoxide dismutase 1 [100
Transcriptions factors 
 Notch1 Notch homologue 1, translocation-associated [101
 MyoD Myogenic factor D [102
Cytokines and growth factors 
 IL-6 Interleukin 6 [103
 FGF21 Fibroblast growth factor 21 [104
TargetDescriptionReference
Antioxidants 
 TXN Thioredoxin [95
 GSR Glutathione reductase [96
 FT Ferritin [97
Enzymes 
 NQO1 NAD(P)H dehydrogenase quinone 1 [98
 HO-1 Haem oxygenase 1 [99
 SOD Superoxide dismutase 1 [100
Transcriptions factors 
 Notch1 Notch homologue 1, translocation-associated [101
 MyoD Myogenic factor D [102
Cytokines and growth factors 
 IL-6 Interleukin 6 [103
 FGF21 Fibroblast growth factor 21 [104

PHARMACOLOGICAL Nrf2 ACTIVATORS

Owing to Nrf2’s major role in antioxidative defence, Nrf2-targeting molecules have been studied intensely in recent years. This has been accelerated by the development of new methods which allow a highly responsive and efficient screening of chemicals that are likely to activate Nrf2.

One of the most promising agents is a group of triterpenoids that are derived from OAs (oleanolic acids). OA is a naturally occurring substance found in olive oil or Salvia, which itself has highly antioxidant capacities. BM (bardoxolone methyl) (also termed CDDO-Me) is a methyl ester derivative of OA and one of the most potent Nrf2 inducers [11,12]. Additionally, BM also inhibits NF-κB (nuclear factor κB) signalling, a major pro-inflammatory pathway, by direct inhibition of IKKβ (inhibitor of NF-κB kinase β) [13]. Thus BM has highly antioxidative and anti-inflammatory properties, which make it a very attractive asset for clinical practice.

Another very interesting substance is DMF (dimethyl fumarate), which activates Nrf2 through an as-yet unknown mechanism. In the early 1990s, DMF was licensed in Germany under the trade name Fumaderm for oral therapy in patients with psoriasis [14], although its beneficial effect was first related to its immunomodulatory properties rather than to Nrf2 modulation [15]. In 2013, DMF (also termed BG-12) was licensed for oral therapy in patients with MS (multiple sclerosis), where Nrf2 induction tackles chronic inflammation and degradation of myelin (see below).

In basic research, isothiocyanates such as SFN (sulforaphane) are very widely used to induce Nrf2 activity in cell culture and animal trials. SFN is an indirect antioxidant which disrupts the Nrf2–Keap1 interaction and thereby promotes expression of ARE-driven genes [16]. These substances are also derived from vegetables such as broccoli, cabbage and mustard [17]. We were able to show that SFN induces Nrf2 activity in naïve cells, whereas it induces apoptosis in inflamed cells via NF-κB inhibition [18]. However, the results in human studies are quite contradictory, as some trials showed beneficial effects of SFN in some diseases such as pancreatic cancer [19], whereas in other trials pharmacological Nrf2 inducers seemed to worsen the outcome as in head and neck tumours [20]. Several ongoing clinical trials are currently investigating the impact of SFN on melanoma, prostate and breast cancer (http://clinicaltrials.gov; NCT01568996, NCT01950143, NCT00982319), as pre-clinical data show that SFN might have anti-tumoral effects by destabilization of microtubules in cancer cells [21].

PHARMACOLOGICAL Nrf2 INHIBITORS

Owing to Nrf2’s cytoprotective capacities, it has not just been considered a target for treatment, but also for prevention of diseases such as cancer. Studies have been conducted with dietary compounds and synthetic substances in order to elucidate whether an Nrf2 boost increases protection against carcinogenic environmental insults (Table 2). However, there is an emerging ‘dark side’ of Nrf2, as recent data have shown a high rate of gain-of-function mutations in the genes for Nrf2 and Keap1 in many cancer types. Nrf2 has highly proliferative characteristics on various cells, suggesting that it can promote cancer [22,23]. Moreover, cancer cells with Nrf2-activating mutations are more resistant to chemotherapies, which indicates that the Nrf2/Keap1 pathway has a role in acquired chemoresistance [24,25].

Table 2
Overview of clinical trials with Nrf2 inducers

Data retrieved from http://clinicaltrials.gov. Abbreviations: BM, bardoxolone methyl; BSE-SFN, broccoli sprout extract sulforaphane; CKD, chronic kidney disease; DMF, dimethyl fumarate; EDSS, expanded disability status scale; FARS, Friedreich's ataxia rating scale; GFR, glomerular filtration rate; IFNβ1a, interferon β1a; MS, multiple sclerosis; NSCLC, non-small-cell lung cancer; PAH, pulmonary artery hypertension; SBS, standard broccoli soup.

DatePhaseDiseaseInterventionAimStatusReference
2006 Advanced solid tumoursLymphoid malignancies Drug: BM Dose escalation study to specify pharmacokinetics and pharmacodynamics Completed [48] NCT00508807 
2007 I, II Hepatic dysfunction Drug: BM Dose escalation study to specify pharmacokinetics and pharmacodynamics Terminated NCT00550849 
2008 II CKD and Type 2 diabetes Drug: BM Effect of BM on GFR over 4 and 8 weeks Completed NCT00664027 
2009 II CKD and Type 2 diabetes Drug: BM against placebo Effect of BM on GFR over 24 and 52 weeks Completed [49] NCT00811889 
2010 II CKD and Type 2 diabetes Drug: BM Effect of new formulation of BM with higher oral bioavailibility on GFR Completed NCT01053936 
2011 III Stage 4 CKD and Type 2 diabetes Drug: BM against placebo Efficacy of BM in slowing down CKD progression Terminated [51] NCT01351675 
2012 Stage 3 CKD and Type 2 diabetes Drug: BM against placebo Effect of BM on GFR (measured by scintigraphy) over 24 weeks Terminated NCT01500798 
2012 CKD and Type 2 diabetes Drug: BM Dose escalation study to specify pharmacokinetics and pharmacodynamics Terminated NCT01549769 
2014 II CKD and Type 2 diabetes Drug: BM l against placebo Effect of BM on GFR over 16 weeks Recruiting NCT02316821 
2014 II PAH Drug: BM against placebo Effect of BM on 6-minute walk test over 16 weeks Recruiting NCT02036970 
2015 II Mitochondrial myopathy Drug: BM against placebo Effect of BM on peak workload during exercise and on 6-minute walk test Not yet recruiting NCT02255422 
2015 II Friedreich's ataxia Drug: BM against placebo Effect of BM on peak workload during exercise and on FARS over 12 weeks Recruiting NCT02255435 
2007 III MS Drug: DMF against placebo against glatiramer acetate Effect of DMF on relapse rate, number of lesions and EDSS over 2 years Completed [89] NCT00451451 
2007 III MS Drug: DMF against placebo Effect of DMF on relapse rate, number of lesions and EDSS over 2 years Completed [90] NCT00420212 
2013 IV MS Drug: DMF Effect of DMF on relapse rate Recruiting NCT01930708 
2014 III Paediatric MS Drug: DMF against IFNβ1a Effect of DMF on size/number of lesions Recruiting NCT02283853 
2014 II Radiation dermatitis Drug: BM lotion versus placebo Effect of BM on skin changes after radiation therapy over 9 weeks Ongoing NCT02142959 
2013 Metastatic NSCLC relapsed melanoma Drug: BM Dose escalation study to determine recommended dose for phase II study Recruiting NCT02029729 
2013  Prostate cancer Drug: SBS Effect of SFN on gene expression in prostate cancer Ongoing NCT01950143 
2009 II Breast cancer Drug: BSE-SFN against placebo (mango juice) Effect of SFN on proliferation (Ki67) and Nrf2 target genes in cancerous tissue Completed NCT00982319 
2014 II Corneal endothelial cell loss Drug: BM ophthalmic suspension against placebo Effect of BM on number of corneal endothelial cells, inflammation and pain over 12 weeks Recruiting NCT02128113 
DatePhaseDiseaseInterventionAimStatusReference
2006 Advanced solid tumoursLymphoid malignancies Drug: BM Dose escalation study to specify pharmacokinetics and pharmacodynamics Completed [48] NCT00508807 
2007 I, II Hepatic dysfunction Drug: BM Dose escalation study to specify pharmacokinetics and pharmacodynamics Terminated NCT00550849 
2008 II CKD and Type 2 diabetes Drug: BM Effect of BM on GFR over 4 and 8 weeks Completed NCT00664027 
2009 II CKD and Type 2 diabetes Drug: BM against placebo Effect of BM on GFR over 24 and 52 weeks Completed [49] NCT00811889 
2010 II CKD and Type 2 diabetes Drug: BM Effect of new formulation of BM with higher oral bioavailibility on GFR Completed NCT01053936 
2011 III Stage 4 CKD and Type 2 diabetes Drug: BM against placebo Efficacy of BM in slowing down CKD progression Terminated [51] NCT01351675 
2012 Stage 3 CKD and Type 2 diabetes Drug: BM against placebo Effect of BM on GFR (measured by scintigraphy) over 24 weeks Terminated NCT01500798 
2012 CKD and Type 2 diabetes Drug: BM Dose escalation study to specify pharmacokinetics and pharmacodynamics Terminated NCT01549769 
2014 II CKD and Type 2 diabetes Drug: BM l against placebo Effect of BM on GFR over 16 weeks Recruiting NCT02316821 
2014 II PAH Drug: BM against placebo Effect of BM on 6-minute walk test over 16 weeks Recruiting NCT02036970 
2015 II Mitochondrial myopathy Drug: BM against placebo Effect of BM on peak workload during exercise and on 6-minute walk test Not yet recruiting NCT02255422 
2015 II Friedreich's ataxia Drug: BM against placebo Effect of BM on peak workload during exercise and on FARS over 12 weeks Recruiting NCT02255435 
2007 III MS Drug: DMF against placebo against glatiramer acetate Effect of DMF on relapse rate, number of lesions and EDSS over 2 years Completed [89] NCT00451451 
2007 III MS Drug: DMF against placebo Effect of DMF on relapse rate, number of lesions and EDSS over 2 years Completed [90] NCT00420212 
2013 IV MS Drug: DMF Effect of DMF on relapse rate Recruiting NCT01930708 
2014 III Paediatric MS Drug: DMF against IFNβ1a Effect of DMF on size/number of lesions Recruiting NCT02283853 
2014 II Radiation dermatitis Drug: BM lotion versus placebo Effect of BM on skin changes after radiation therapy over 9 weeks Ongoing NCT02142959 
2013 Metastatic NSCLC relapsed melanoma Drug: BM Dose escalation study to determine recommended dose for phase II study Recruiting NCT02029729 
2013  Prostate cancer Drug: SBS Effect of SFN on gene expression in prostate cancer Ongoing NCT01950143 
2009 II Breast cancer Drug: BSE-SFN against placebo (mango juice) Effect of SFN on proliferation (Ki67) and Nrf2 target genes in cancerous tissue Completed NCT00982319 
2014 II Corneal endothelial cell loss Drug: BM ophthalmic suspension against placebo Effect of BM on number of corneal endothelial cells, inflammation and pain over 12 weeks Recruiting NCT02128113 

Although no pharmacological Nrf2 inhibitors have yet been tested in clinical trials, many promising substances have been tested in laboratory trials. For one, alkaloid trigonelline, a substance retrieved from coffee beans, reduces nuclear accumulation of Nrf2 and thereby inhibits transcription of Nrf2-driven genes [26]. The substance brusatol, extracted from the evergreen shrub Brucea javanica, is an agent that enhances ubiquitination of Nrf2 and therefore reduces cytoplasmic Nrf2 levels [27].

From a clinical point of view, acquired chemoresistance is a very common and difficult challenge. Hence pharmacological Nrf2 inhibitors could be administered concurrently with chemotherapy in order to prevent resistance formation. Compared with Nrf2-inducing substances, data on Nrf2 inhibitors are still preliminary and more basic research as well as clinical trials are necessary to assess the actual effect of pharmacological Nrf2 inhibition.

Nrf2 IN LIVER DISEASE

Basics

Since the liver is the central detoxifying organ of the human body, it is constantly exposed to high levels of ROS which occur during detoxification and metabolization. Thus hepatocytes express high levels of Nrf2 in order to maintain homoeostasis and tissue integrity in the liver [28]. Several liver diseases are linked to a disruption of antioxidant defence, including alcoholic and non-alcoholic liver disease, viral hepatitis and hepatocellular carcinoma (reviewed in [29]).

For viral infections, it has been shown that permanent overproduction of viral proteins can result in increased levels of free radicals and other ROS [30]. HBV (hepatitis B virus), via its association with mitochondria, induces oxidative stress, which in turn activates a series of transcription factors, such as NF-κB or Raf-1 (rapidly accelerated fibrosarcoma-1) [31]. Especially during early stages of the infection process, HCV (hepatitis C virus) proteins induce a strong Nrf2 up-regulation [32]; HO-1, a main target gene of Nrf2, seems to be crucial for the defence against HCV-induced cellular damage [33]. NAFLD (non-alcoholic fatty liver disease) represents one of the fastest rising disease entities causing CLI (chronic liver injury), especially in developed countries. Accumulation of triacylglycerols in the liver impairs the mitochondrial respiratory chain activity and thus results in ROS overproduction and depletion of mitochondrial glutathione. NASH (non-alcoholic steatohepatitis) pathogenesis also includes reduced SOD (superoxide dismutase) and increased lipid peroxidation in hepatocytes. Nrf2 also modulates genes involved in metabolic regulation, which play an important role in nutrient homoeostasis [34]. Therapeutically, it might be reasonable to suppress hepatic oxidative stress, thereby preventing the progression of NAFLD. Experimental studies show that, e.g., probiotic compounds can induce Nrf2 and its target antioxidative enzymes which results in an amelioration of disease activity [35].

For ethanol metabolism, it is known that acetaldehyde production by alcohol dehydrogenase results in glutathione (GSH) depletion, lipid peroxidation and the generation of ROS and acetaldehyde adducts [36]. Here, Nrf2 dysregulation of GSH synthesis contributes to the pathogenesis of alcoholic liver disease. Free radicals play another part in the pathogenesis of liver damage, as chronic ethanol treatment increases the production of ROS, lowers cellular antioxidant levels and enhances oxidative stress in the liver.

Nrf2 and oxidative stress do not only play a role during CLI. For acetaminophen-induced toxicity it is reported that the production of radicals and ROS is triggered. Nrf2 activation does provide protective effects; however, most of the available data come from mouse experiments [37]. So far, evidence from human cells and organisms is sparse. A recent study performed in a human hepatic stellate cell line demonstrated that SFN attenuates hepatic fibrosis through Nrf2-mediated inhibition of TGF-β (transforming growth factor-β) signalling [38]. Moreover, Nrf2 activators could abolish liver fibrosis in a rat model of NASH [39] through the protection of hepatic cells from oxidative damage.

Despite these promising data, recent studies have shown that persistent Nrf2 activation leads to inflammation and fibrosis in mice with defective autophagy; moreover, a considerable portion of liver cancers have somatic Keap1 mutations, suggesting that Nrf2 might protect cancer cells or even promote the development of cancer [23,40,41]. Taken together, studies indicate that Nrf2 induction certainly seems to have a protective influence on liver diseases; however, the effect of long-term Nrf2 overexpression with regard to tumorigenesis remains unclear.

Clinical implications

Despite the liver's tremendous regenerative capacities after acute injury, chronic liver diseases are a widespread clinical challenge as viral hepatitis and alcoholic/non-alcoholic liver disease have an increasing prevalence. To date, only one clinical trial has been initiated that has investigated the influence of Nrf2 induction via BM on liver disease (NCT00550849). However, this study was terminated early for undisclosed reasons. Hence there is still a need for randomized controlled trials to clarify the possible benefits of Nrf2 inducers in liver disease.

Nrf2 IN KIDNEY DISEASE

Basics

Several kidney injury models in Nrf2-KO (knockout) mice have revealed a greater susceptibility for renal damage than in WT (wild-type) mice. Nrf2-KO mice fed with a high glucose diet rapidly develop diabetic nephropathy [42,43]. Hypertensive kidney disease is also associated with Nrf2 deficiency [44]. Other kidney diseases such as focal segmental glomerulosclerosis [45] or renal fibrosis [46] are also furthered by an impaired Nrf2 activation, leading to disease progression. In fact, aged Nrf2-KO mice constitutively develop a lupus-like autoimmune nephritis, which suggests a role for Nrf2 in autoimmune disease [47].

Clinical implications

Diabetic nephropathy is the most common cause of CKD (chronic kidney disease) in developed and developing countries, followed by hypertensive kidney disease. Currently, the first-line therapies for most patients with CKD are ACE (angiotensin-converting enzyme) inhibitors such as ramipril or angiotensin receptor 1 blockers such as ibesartan [48]. However, all available therapeutic regiments only slow progression to ESRD (end-stage renal disease), meaning a reduction in GFR (glomerular filtration rate) below 15 ml/min (equivalent to stage 5 CKD). Apart from renal transplantation, no treatment can improve kidney function in a sustained way.

As a lack of Nrf2 activity seems to be pivotal for progression of kidney disease, an Nrf2-inducing drug is an obvious therapeutic option. The agent BM received a great amount of attention in the recent past when Hong et al. [49] presented a Phase I trial which aimed to objectify an anti-tumour effect of Nrf2 induction on solid tumours; surprisingly, the authors observed a significant increase in GFR, suggesting that BM could be beneficial in CKD.

BM was the first drug with the capacity to significantly increase GFR by approximately 10 ml/min in a cohort of 227 CKD patients (BEAM study; NCT00811889) [50]. However, the highly acclaimed Phase III BEACON trial with 2185 patients had to be terminated owing to an increase in deaths from cardiovascular causes in the verum group (NCT01351675) [51,52]. The high rate of cardiovascular events could be attributed to a modulation of the endothelin pathway: BM decreased endothelin-1 secretion and ETA (endothelin receptor type A) receptor expression in pre-clinical settings [53]. Decreased levels of endothelin promote fluid retention [54,55] (reviewed in [56]), an effect that led to fluid overloading in CKD patients with subsequent heart failure in the BEACON trial [57,58]. This observation can be attributed to BM's inhibitory effect on NF-κB, which normally targets the endothelin pathway [59].

Taken together, BM is a very potent Nrf2 inducer that has beneficial effects on CKD progression or even renal regeneration [60]. However, the high rate of cardiovascular events in ESRD patients means that further studies are needed to find out which CKD patients will have the highest benefit from Nrf2 induction. A promising approach could be the administration of BM in early diabetic CKD patients in order to halt disease progression; in December 2014, a randomized controlled Phase II study was enrolled with BM against placebo in diabetic CKD patients without cardiovascular disease or hypertension higher than 160 mmHg (NCT02316821). Compared with the BEACON trial design, which included critical patients with high rates of co-morbidities, this study focuses on relatively stable diabetic patients, which should reduce the occurrence of cardiovascular events and highlight Nrf2’s influence on renal function.

Nrf2 IN PULMONARY DISEASE

Basics

As the lung is constantly exposed to oxidants from cigarette smoke, air pollutants or infections, efficient antioxidative signalling is crucial for its integrity. The most common pulmonary condition is COPD (chronic obstructive pulmonary disease), which is characterized by chronic inflammation and subsequent remodelling of small airways, resulting in pulmonary emphysema (reviewed in [61]). It has been shown that Nrf2-deficient mice exposed to cigarette smoke have a much higher susceptibility to COPD and emphysema compared with WT Nrf2 mice [6264]. The same observation was made in animal models of PAH (pulmonary artery hypertension), a disease caused by narrowing of blood vessels and ultimately right heart failure [65]. Pharmacological Nrf2 induction reduced the rate of right heart failure in mice with PAH [66]; however, it is not certain whether it also affects vascular remodelling. Other diseases include ventilation-associated lung injury, where Nrf2 regulates inflammation [67,68], and ALI (acute lung injury)/ARDS (acute respiratory distress syndrome), where Nrf2 has a protective influence on lung integrity and survival rates in mice [6071].

Clinical implications

The number of clinical studies with Nrf2 inducers in patients with pulmonary diseases is still very limited. After the BEACON trials, it was observed that the Nrf2 inducer BM decreased endothelin secretion and ETA expression. Endothelin is a main target of therapy in pulmonary hypertension, as it causes vasoconstriction of pulmonary vessels, therefore drugs such as bosentan, which directly antagonize endothelin receptors, are a widely used option in PAH (reviewed in [72]). Recently, a Phase II study was launched with BM against placebo in PAH patients to determine the safety and efficacy after 16 weeks of study participation (NCT02036970).

Nrf2 IN NEURODEGENERATIVE DISEASE

Basics

A growing body of evidence indicates a critical involvement of mitochondrial dysfunction and oxidative stress in the pathogenesis of distinct neurodegenerative diseases such as PD (Parkinson's disease), AD (Alzheimer's disease) and MS [7377].

In addition, an imbalance between the generation of free radicals and antioxidant defences has been linked to neuronal damage and disease progression in other neurological disorders such as stroke [78].

In several experimental settings, Nrf2 induction did indeed improve the outcome of neurodegenerative conditions. For one, SFN administration displayed neuroprotective effects and reduced microgliosis and astrogliosis in a PD mouse model [79]. Likewise, SFN also ameliorated cognitive impairment in mice, although Aβ (amyloid β-peptide) aggregation was not reduced by Nrf2 induction [80]. In an in vivo approach, we showed that Nrf2-inducing flavonoids and kavalactones protect neuronal cells in cell-based models for PD and AD [81,82].

Apart from these frequently investigated pathologies, there are also rare neurological conditions that have caught the attention of Nrf2 researchers: FA (Friedreich's ataxia), a condition that leads to early progressive neurodegeneration due to increased intracellular oxidative stress, was shown to be linked with impaired nuclear Nrf2 translocation [83]. Increased oxidative stress is also the main pathophysiological element in MM (mitochondrial myopathy), where disruption of mitochondria leads to increased sensitivity to oxidative stress in skeletal muscle cells and subsequently to a progressive destruction of myocytes [84].

Clinical implications

MS is a complex and heterogeneous inflammatory disease of the CNS (central nervous system) and the most important non-traumatic cause of neurological disability in young adults [85]. Histopathologically, MS is characterized by inflammation, the destruction of myelin sheaths and a loss of myelinating oligodendrocytes. However, and despite intensive research, the aetiology of MS is only partly understood. It is assumed today that oxidative stress and pro-inflammatory stimuli are important players in its pathogenesis [86]. Oxidative stress and injury are likely to participate in the induction of demyelination and neurodegeneration in both the relapsing–remitting and progressive stages of MS and this oxidative stress is mainly driven by inflammation and oxidative burst in activated microglia [87].

From a clinical point of view, MS can be classified according to its progressive form, with most patients suffering from a relapsing–remitting disease course, characterized by reoccurring phases of neural deficiency and subsequent periods of remission.

For a long time, cortisone and interferons were the backbone of MS therapy; however, in recent years, several new oral agents have been licensed for treatment [88]; among them, DMF was the first Nrf2-targeting drug to be licensed by the U.S. FDA (Food and Drug Administration). DMF has been licensed for treatment of psoriasis in Germany since the 1990s, but it was not until 2006 that physicians observed a reduction in relapse rates in MS patients whose psoriasis was treated with DMF [89]. This observation and a number of publications on DMF and Nrf2 induction led to large Phase III trials, the CONFIRM and DEFINE studies. These studies compared DMF with placebo or accordingly with glatiramer acetate, one of the first-line drugs in relapsing MS [9092]. Although the Nrf2-inducing properties of DMF have been established in vitro and in vivo in animal trials, the precise benefit of Nrf2 induction in MS patients has not yet been substantiated. Nevertheless, the studies showed a significant reduction in relapse rate, disability progression and brain lesions. The drug was ultimately licensed for patients with relapsing–remitting MS in 2013 by the FDA, EMA (European Medicines Agency) and PMDA (Pharmaceuticals and Medical Devices Agency).

In autumn 2014, a Phase II study was launched with patients with FA who were to be treated once more with the Nrf2 inducer BM in order to assess whether Nrf2 can alter the outcome of this fatal disease (NCT02255435). Another study with a comparable design is soon to be launched in patients with MM, who will also be treated with BM (NCT02255422). Although FA and MM are quite rare diseases, these clinical trials will provide a better understanding of BM's pharmacodynamics and the long-term consequences of systemic Nrf2 induction.

CONCLUDING REMARKS

Oxidative stress and damage are hallmarks for the progression of many degenerative diseases. Antioxidative mechanisms are therefore a promising target for pharmacological interventions; as Nrf2 is a major regulator of cellular antioxidative defence, its up-regulation leads to induction of a broad set of cytoprotective target genes. A large set of in vivo trials has shown that Nrf2 induction modifies a variety of conditions and protects against disease progression. The present review has highlighted the most important clinical trials that have investigated the efficacy of pharmacological Nrf2 induction in various conditions (Table 3). Currently, DMF and BM are the two most potent Nrf2-inducing compounds for clinical use. Whereas DMF has already been proved to be a safe and powerful drug for MS therapy, BM still has major safety concerns despite the early promising findings in CKD treatment. Moreover, it is still unclear whether a sustained systemic Nrf2 induction furthers the development of other diseases such as cancer [93]. Hence more controlled studies are necessary to assess possible indications for Nrf2-targeting therapies and to clarify the emerging safety issues.

Table 3
Summary of Nrf2/Keap1-related health disorders

Abbreviations: ETA, endothelin receptor type A; IL, interleukin; ROS, reactive oxygen species; TNFα, tumour necrosis factor.

DiseasePathomechanismImplications for Nrf2 modulationReference(s)
Psoriasis Chronic inflammatory disease of the skin; excessive keratinocyte proliferation with epidermal hyperplasia Dimethyl fumarate*: Nrf2 up-regulation→anti-inflammatory+antioxidative→reduction in pro-proliferative cytokines such as TNFα, IL-6 and IL-22 [106
Multiple sclerosis Chronic inflammatory disease of the central nervous system; demyelination and blood–brain barrier disruption Dimethyl fumarate*: Nrf2 up-regulation→anti-inflammatory+antioxidative→re-myelination [107
Diabetic nephropathy/chronic kidney disease Diabetes-induced increase in ROS, leading to disruption of glomeruli Bardoxolone methyl: Nrf2 up-regulation→anti-inflammatory+antioxidative→regeneration of glomeruli→increase in GFR [108
Pulmonary hypertension Vasoconstriction of pulmonary vessels with subsequent right heart failure Bardoxolone methyl: Nrf2 up-regulation+reduced endothelin and ETA expression→pulmonary vasodilatation [66
Friedreich's ataxia Mutation of frataxin gene, leading to iron accumulation and excessive oxidative stress Bardoxolone methyl: Nrf2 up-regulation→anti-inflammatory+antioxidative [83,84
Mitochondrial myopathy Mitochondrial dysfunction→ROS accumulation→muscle degeneration   
Cancer Uncontrolled cell proliferation Sulforaphane, bardoxolone methyl: Nrf2 up-regulation+NF-κB down-regulation→restoration of anti-tumour immunity [24
  Trigonelline, brusatol: Nrf2 inhibition→higher susceptibility to ROS→decreased chemoresistance  
Corneal endothelial cell loss Loss of corneal endothelial cells due to oxidative stress and inflammation after cataract surgery→clouding and loss of vision Bardoxolone methyl: Nrf2 up-regulation→anti-inflammatory and antioxidative [109
DiseasePathomechanismImplications for Nrf2 modulationReference(s)
Psoriasis Chronic inflammatory disease of the skin; excessive keratinocyte proliferation with epidermal hyperplasia Dimethyl fumarate*: Nrf2 up-regulation→anti-inflammatory+antioxidative→reduction in pro-proliferative cytokines such as TNFα, IL-6 and IL-22 [106
Multiple sclerosis Chronic inflammatory disease of the central nervous system; demyelination and blood–brain barrier disruption Dimethyl fumarate*: Nrf2 up-regulation→anti-inflammatory+antioxidative→re-myelination [107
Diabetic nephropathy/chronic kidney disease Diabetes-induced increase in ROS, leading to disruption of glomeruli Bardoxolone methyl: Nrf2 up-regulation→anti-inflammatory+antioxidative→regeneration of glomeruli→increase in GFR [108
Pulmonary hypertension Vasoconstriction of pulmonary vessels with subsequent right heart failure Bardoxolone methyl: Nrf2 up-regulation+reduced endothelin and ETA expression→pulmonary vasodilatation [66
Friedreich's ataxia Mutation of frataxin gene, leading to iron accumulation and excessive oxidative stress Bardoxolone methyl: Nrf2 up-regulation→anti-inflammatory+antioxidative [83,84
Mitochondrial myopathy Mitochondrial dysfunction→ROS accumulation→muscle degeneration   
Cancer Uncontrolled cell proliferation Sulforaphane, bardoxolone methyl: Nrf2 up-regulation+NF-κB down-regulation→restoration of anti-tumour immunity [24
  Trigonelline, brusatol: Nrf2 inhibition→higher susceptibility to ROS→decreased chemoresistance  
Corneal endothelial cell loss Loss of corneal endothelial cells due to oxidative stress and inflammation after cataract surgery→clouding and loss of vision Bardoxolone methyl: Nrf2 up-regulation→anti-inflammatory and antioxidative [109

*Compound is approved for treatment of this condition.

†Pre-clinical data.

Abbreviations

     
  • AD

    Alzheimer's disease

  •  
  • ARE

    antioxidant-response element

  •  
  • BM

    bardoxolone methyl

  •  
  • CKD

    chronic kidney disease

  •  
  • CLI

    chronic liver injury

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • Cul

    cullin

  •  
  • DMF

    dimethyl fumarate

  •  
  • ESRD

    end-stage renal disease

  •  
  • ETA

    endothelin receptor type A

  •  
  • FA

    Friedreich's ataxia

  •  
  • FDA

    Food and Drug Administration

  •  
  • GFR

    glomerular filtration rate

  •  
  • GSK3β

    glycogen synthase kinase 3β

  •  
  • HCV

    hepatitis C virus

  •  
  • HO-1

    haem oxygenase-1

  •  
  • Keap1

    Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1

  •  
  • KO

    knockout

  •  
  • MM

    mitochondrial myopathy

  •  
  • MS

    multiple sclerosis

  •  
  • NAFLD

    non-alcoholic fatty liver disease

  •  
  • NASH

    non-alcoholic steatohepatitis

  •  
  • NF-κB

    nuclear factor κB

  •  
  • Nrf2

    nuclear factor erythroid 2-related factor 2

  •  
  • OA

    oleanolic acid

  •  
  • PAH

    pulmonary artery hypertension

  •  
  • PD

    Parkinson's disease

  •  
  • Rbx

    RING box protein

  •  
  • ROS

    reactive oxygen species

  •  
  • SFN

    sulforaphane

  •  
  • SQSTM1

    Sequestome-1

  •  
  • β-TrCP

    β-transducin repeat-containing protein

  •  
  • WT

    wild-type

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