REVIEW

published: 25 June 2021

doi: 10.3389/fendo.2021.598005

NRF2-Related Epigenetic
Modifications in Cardiac and
Vascular Complications of
Diabetes Mellitus
Jie Wang 1†, Mengjie Xiao 1†, Jie Wang 1†, Shudong Wang 2, Jingjing Zhang 3, Yuanfang
Guo 1, Yufeng Tang 4 and Junlian Gu 1*
1 School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, China, 2 Department of Cardiology, The First

Hospital of Jilin University, Changchun, China, 3 Department of Cardiology, The First Hospital of China Medical University,
and Department of Cardiology at the People’s Hospital of Liaoning Province, Shenyang, China, 4 Department of Orthopedic
Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, China

Edited by:
Diabetes mellitus (DM) is a highly prevalent chronic disease that is accompanied with
Jared Rutter, serious complications, especially cardiac and vascular complications. Thus, there is an
The University of Utah, United States urgent need to identify new strategies to treat diabetic cardiac and vascular complications.
Reviewed by: Nuclear factor erythroid 2-related factor 2 (NRF2) has been verified as a crucial target for
Ziping Jiang,
First Affiliated Hospital of Jilin the prevention and treatment of diabetic complications. The function of NRF2 in the
University, China treatment of diabetic complications has been widely reported, but the role of NRF2-
Shengzhu Zhou,
Jilin University, China
related epigenetic modifications remains unclear. The purpose of this review is to
Xavier Prieur, summarize the recent advances in targeting NRF2-related epigenetic modifications in
INSERM U1087 L’unité de recherche the treatment of cardiac and vascular complications associated with DM. We also discuss
de l’institut du thorax, France
agonists that could potentially regulate NRF2-associated epigenetic mechanisms. This
*Correspondence:
Junlian Gu review provides a better understanding of strategies to target NRF2 to protect against
junlian_gu@sdu.edu.cn DM-related cardiac and vascular complications.
†
These authors have contributed
Keywords: NRF2, epigenetic modifications, NRF2 activators, diabetic cardiac complication, diabetic
equally to this work
vascular complication

Specialty section:
This article was submitted to
Diabetes: Molecular Mechanisms, INTRODUCTION
a section of the journal
Frontiers in Endocrinology Diabetes mellitus (DM) is a metabolic disorder caused by genetic and environmental factors. DM is
Received: 23 August 2020 the third-largest non-communicable disease, following only cardiovascular diseases and malignant
Accepted: 26 April 2021 tumors (1, 2). The majority of DM-related morbidity and mortality is due to cardiac and vascular
Published: 25 June 2021 diseases triggered by long-term exposure to high blood glucose (3). These negative effects of
Citation: hyperglycemia may persist even after achieving glycemic control, known as “metabolic memory”,
Wang J, Xiao M, Wang J, Wang S, which is related to epigenetic modifications (4, 5). Thus, it is an urgent requirement to find novel
Zhang J, Guo Y, Tang Y and Gu J
epigenetics-related treatment strategies to prevent and protect against DM-induced cardiac and
(2021) NRF2-Related Epigenetic
Modifications in Cardiac and Vascular
vascular complications.
Complications of Diabetes Mellitus. The pathological characteristics of DM and its related complications have been extensively
Front. Endocrinol. 12:598005. investigated. Specifically, oxidative stress, apoptosis, and inflammation have been reported to be
doi: 10.3389/fendo.2021.598005 involved in the development of DM-induced complications. Notably, oxidative stress is regarded as a

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Wang(b) et al. NRF2 in Diabetic Complications

major factor in the pathogenesis of diabetic complications (6). regarding the effects of NRF2-related epigenetic modifications on
Strong evidence indicates that epigenetics plays a significant role in the regulation of oxidative stress (summarized in Figure 1).
regulating oxidative stress. Nuclear factor erythroid 2-related factor DNA methylation is a dynamically equilibrated process that is
2 (NRF2), encoded by nfe2l2 (7), is one of the major regulators of controlled by DNA methyltransferases (DNMTs) and DNA
oxidative stress (8). Numerous studies have explored the key role of demethylation enzymes (19). A growing number of studies indicate
NRF2-related epigenetic modifications in various disease models (9, that altered DNA methylation of nfe2l2 plays an important role in
10). NRF2-correlated epigenetic modifications have been proposed regulating oxidative stress induced by various diseases. For example,
to decrease the occurrence and progression of DM-related cardiac in 12-O-tetradecanoylphorbol-13-acetate-induced carcinogenesis of
and vascular complications via inhibiting oxidative stress (11, 12). mouse skin epidermal JB6P+ cells, reduced DNA methylation of the
However, the exact effects of NRF2-related epigenetic modifications first 15 CpG sites in the Nfe2l2 promoter region by taxifolin could
in DM and its related complications require further investigation. suppress cellular oxidative stress via inhibiting the expression of
To date, there is limited literature focused on NRF2-related DNMT1, DNMT3a, and DNMT3b (18). Consistent with this study,
epigenetic modifications and NRF2 agonists in the treatment of Zhao et al. reported that sulforaphane plays an antioxidative role by
DM-related cardiac and vascular complications (13–15). The reducing DNA methylation of the Nfe2l2 promoter through
purpose of this review is to provide a retrospective summary decreasing the levels of DNMTs in a cellular Alzheimer’s disease
of NRF2-associated epigenetic modifications in DM-related model (20). Conversely, in human ovarian cancer cells, increased
cardiac and vascular complications and discuss NRF2 agonists DNA methylation on the NFE2L2 promoter by the combined
that could potentially be used to regulate NRF2-associated administration of trastuzumab and pertuzumab inhibited the
epigenetic mechanisms. expression of NRF2 and weakened its antioxidant function to
perform an anti-cancer effect (21).
Apart from DNA methylation, histone modifications are key
THE EFFECTS OF NRF2-RELATED epigenetic mechanisms in the regulation of oxidative stress, as
EPIGENETIC MODIFICATIONS ON THE they affect gene expression by modifying the chromatin structure
REGULATION OF OXIDATIVE STRESS (22, 23). Recently, Yang et al. found that the administration of
corosolic acid has an antioxidant effect in TRAMP-C1 prostate
Many studies have demonstrated that oxidative stress is a major cells, which might be associated with increased acetylation of
risk factor in multiple diseases (16, 17). Changes in epigenetic histone H3 lysine 27 (H3K27ac) and decreased trimethylation of
modifications can control phenotype and progression of diseases H3K27 (H3K27me3) in the Nfe2l2 promoter region. The authors
by modulating oxidative stress (18). Here, we review the literature proposed that corosolic acid exerts its effect by inhibiting protein

FIGURE 1 | NRF2-related epigenetic mechanisms in the regulation of oxidative stress. Taxifolin and sulforaphane reduce DNA methylation of the Nfe2l2 promoter
region to exert antioxidant effect by inhibiting the expression of DNMTs. Corosolic acid increases acetylation of H3K27 in the Nfe2l2 promoter region to exert
antioxidant effect by inhibiting the expression of HDACs. Dexamethasone enhances GR recruitment to AREs to block NRF2-dependent CBP recruitment and histone
acetylation at AREs, which inhibits the transcriptional activation of NRF2 target genes and reduces its antioxidant function. miR-140-5p, miR-153, and miR-144 bind
to the 3’ UTR of NRF2 to aggravate oxidative stress by inhibiting NRF2 expression. NRF2, nuclear factor erythroid 2-related factor 2; miR, microRNA; DNMTs, DNA
methyltransferases; HDACs, histone deacetylases; GR, glucocorticoid receptor; CBP, CREB-binding protein; ARE, antioxidant response element; SOD, superoxide
dismutase; CAT, catalase; Gclm, glutamate-cysteine ligase modifier; G6pdx, glucose-6-phosphate dehydrogenase X-linked; 3’ UTR, 3’ untranslated region.

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Wang(b) et al. NRF2 in Diabetic Complications

expression of histone deacetylases (HDACs) (9). Another study epigenetic mechanisms may serve as effective approachs for
using human embryonic kidney (HEK293T) and mouse treating various diseases related to oxidative stress.
hepatocellular carcinoma (Hepalclc7) cells pointed out that
dexamethasone treatment enhanced glucocorticoid receptor
(GR) recruitment to antioxidant response elements (AREs) NRF2-RELATED EPIGENETIC
region and subsequently blocked NRF2-dependent CREB- MODIFICATIONS IN DIABETIC CARDIAC
binding protein (CBP) recruitment and histone acetylation at COMPLICATIONS
AREs, which inhibited the transcriptional activation of NRF2
target genes and reduced its antioxidative function (23). As one of the major complications of DM, diabetic cardiac
MicroRNAs (miRNAs) are 18–26 bp non-coding RNAs complications are closely related to the occurrence of heart failure
(ncRNAs) that have been reported to play a significant role in and poor prognosis of DM patients (28, 29). In recent years, a series
regulating oxidative stress (24, 25). Moreover, miRNAs have of studies have confirmed that NRF2-related epigenetic
been verified to be involved in NRF2 regulation. Zhao et al. modifications play a vital role in the prevention and treatment of
reported that miR-140-5p aggravated adriamycin-induced diabetic cardiac complications (summarized in Figure 2).
myocardial oxidative stress by inhibiting the expression of
NRF2 (25). Similarly, miR-153 can increase reactive oxygen Diabetic Myocardial Ischemia-Reperfusion
species production to further aggregate oxygen-glucose Injury
deprivation and reoxygenation-induced cardiomyocyte Sirtuin1 (Sirt1) is a nicotinamide adenine dinucleotide (NAD+)-
apoptosis by repressing the NRF2/heme oxygenase-1 (HO-1) dependent deacetylase that plays a vital role in regulating NRF2
signaling pathway (26). Furthermore, a reduction in NRF2 expression in the treatment of diabetic myocardial ischemia-
expression caused by miR-144 can exacerbate oxidative stress reperfusion (I/R) injury. For instance, Zhang et al. demonstrated
in erythrocytes from patients with homozygous sickle cell disease that Sirt1 can enhance NRF2 nuclear translocation to prevent
(27). Thus, therapeutic strategies targeting NRF2-associated diabetic myocardial I/R injury in a diabetic Sprague Dawley rat

FIGURE 2 | NRF2-related possibly epigenetic mechanisms in diabetic cardiac complications. Inactivation of the Sirt1/NRF2/HO-1 pathway by miR-34a might cause
ER stress in diabetic myocardial I/R injury. miR-24-3p might activate NRF2 by inhibiting the expression of Keap1 to exert an anti-apoptosis effect in diabetic
myocardial I/R injury. CPDT can activate the NRF2/HO-1 pathway by inhibiting miR-503 to reduce oxidative stress in DCM. Methylation of the nfe212 promoter might
inactivate NRF2 and its downstream targets SREBP-1c and FAS to cause lipid accumulation in DCM. NRF2, nuclear factor erythroid 2-related factor 2; miR,
microRNA; Sirt1, Sirtuin1; HO-1, heme oxygenase-1; SREBP-1c, Sterol regulatory element-binding transcription factor 1c; FAS, fatty acid synthase; CPDT, 5,6-
dihydrocyclopenta-1,2-dithiole-3-thione; Keap1, Kelch-like ECH-associated protein 1; ER, endoplasmic reticulum.

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Wang(b) et al. NRF2 in Diabetic Complications

model (30). Another study reported that Sirt1 deacetylated and macrovascular complications include cardiovascular diseases,
reduced the ubiquitination of NRF2 in advanced glycation-end cerebrovascular diseases, and peripheral vascular diseases. The
products-treated glomerular mesangial cells (GMCs) (31). These microvascular complications include diabetic retinopathy (DR)
studies imply that deacetylation of NRF2 by Sirt1 might be a and diabetic nephropathy (DN). NRF2-related epigenetic
potential mechanism underlying NRF2 nuclear translocation. modifications have been verified to exert a key role in diabetic
miRNAs have also been verified as common regulators of Sirt1. vascular complications (summarized in Figure 3).
For example, crocin can relieve myocardial I/R-related
endoplasmic reticulum (ER) stress through modulating the DM-Related Arterial Injuries
miR-34a/Sirt1/NRF2 signaling pathway in primary neonatal Arterial injury is a common vascular complication in patients with
mouse cardiomyocytes (32). Thus, we further speculate that DM. Endothelial dysfunction is the critical manifestation of diabetic
the miR-34a/Sirt1/NRF2 pathway might be involved in the vascular complications, followed by increased oxidative stress and
prevention and treatment of diabetic myocardial I/R injury. inflammation (41). Sodium butyrate (NaB) is an HDAC inhibitor
Moreover, Xiao et al. further demonstrated that luteolin that has been shown to increase the occupancy of both Nfe2l2’s
modulates the Kelch-like ECH-associated protein 1 (Keap1)/ transcription factor aryl hydrocarbon receptor (AHR) and histone
NRF2 axis to inhibit oxidative stress, thus attenuating diabetic acetylase P300 at the promoter region of the Nfe2l2. Binding of these
myocardial I/R injury (33). miR-24-3p has also been shown to factors promotes the transcriptional activation of Nfe2l2, thus
regulate the Keap1/NRF2 pathway in myocardial I/R injury (34). protecting against aortic endothelial dysfunction in HG-treated
Thus, it is possible that miR-24-3p may act upstream of Keap1/ endothelial cells (ECs) (41). Some studies also revealed that NRF2
NRF2 pathway to alleviate diabetic myocardial I/R injury. regulation by miRNAs may play a critical role in diabetic arterial
injuries. For instance, miR-24 has been shown to stimulate the
Diabetic Cardiomyopathy NRF2/HO-1 signaling pathway to prevent oxidative stress in HG-
NRF2-associated epigenetic modifications have been shown to act stimulated vascular smooth muscle cells (VSMCs) (42). In human
as crucial mechanisms in diabetic cardiomyopathy (DCM), with umbilical vein ECs treated with oxidized low-density lipoprotein,
some literature indicating that epigenetic modifications can miR-140-5p can suppress the expression of NRF2 to aggravate
promote DCM, while other studies suggest that they inhibit DCM. atherosclerosis (AS)-related oxidative stress (43). Additionally,
Methylation of the nfe2l2 promoter might be a potential Hur et al. have shown that the NRF2/ARE axis can activate
contributor to the incidence and development of DCM. Wang the downstream antioxidant enzyme NADPH quinone
et al. reported that cardiac NRF2 expression was significantly oxidoreductase-1 (NQO-1) in VSMCs treated with HG and in a
decreased in a DM mouse model (35). Meanwhile, another study rat model of DM-induced AS (44). These studies provide evidence
showed that the methylation level of the Nfe2l2 promoter was that upregulation of the NRF2/ARE axis by the inhibition of miR-
increased but the gene and protein expression of NRF2 was 140-5p may emerge as a potential therapeutic strategy for treating
decreased under high glucose (HG) condition (36). Thus, we diabetic AS.
speculate that decreased expression of NRF2 may be related to In both HG-treated GMCs and diabetic mice, upregulation of
methylation of the nfe2l2 promoter in DCM. Sirt1 expression can activate NRF2 (45). Meanwhile, another
ncRNAs also play a major role in DCM through targeting study indicated that the inhibition of miR-217 could enhance
NRF2. In HG-stimulated rat and mouse cardiomyocytes models, Sirt1 expression in oxidized low−density lipoprotein treated
the inhibition of miR-144, miR-155, and miR-503 can active THP-1 cells (46). Therefore, we speculate that miR-217 might
NRF2 to attenuate cellular oxidative stress and reduce modulate the Sirt1/NRF2 pathway in diabetic AS progression.
cardiomyocyte apoptosis to prevent DCM (12, 37, 38). Furthermore, a study by Xie et al. showed that Keap1
Recently, Gao et al. found that long ncRNA (lncRNA) HOX sulfhydrylation at Cys151 and NRF2 activation by hydrogen
transcript antisense RNA (HOTAIR) and Sirt1 were sulfide could inhibit oxidative stress to attenuate DM-induced
downregulated but miR-34a was upregulated in diabetic hearts AS both in vitro and in vivo, which indicates that Keap1/NRF2
and HG-stimulated H9c2 cells, while overexpression of lncRNA signaling is a critical regulator of diabetic AS (47). The Keap1/
HOTAIR protected against DCM via increasing Sirt1 expression NRF2 pathway has also been reported to be regulated by miR-
by sponging miR-34a (39). Furthermore, the Sirt1/NRF2 200a to ameliorate oxidative stress in a type II DN rat model,
pathway was shown to play a role in improving DCM via which highlights the important function of miR-200a in the
alleviating myocardial oxidative stress (40). However, whether regulation of Keap1/NRF2 pathway (48). Based on the literature
NRF2 can be regulated by the lncRNA HOTAIR/miR-34a/Sirt1 reviewed here, we suppose that the miR-200a/Keap1/NRF2
pathway in the treatment of DCM needs to be further explored. signaling pathway could be a new pharmacological target to
prevent diabetic AS.

NRF2-RELATED EPIGENETIC Diabetic Blood-Brain Barrier Disruption

MODIFICATIONS IN DIABETIC VASCULAR The blood-brain barrier (BBB) is the main internal barrier of the
COMPLICATIONS human body. It is responsible for regulating the neural
microenvironment, as well as maintaining the stability of the
Diabetic vascular complications can be divided into intracerebral environment and the normal physiological state of
macrovascular and microvascular complications. The the central nervous system (49, 50). Recently, a series of studies

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Wang(b) et al. NRF2 in Diabetic Complications

FIGURE 3 | NRF2-related epigenetic mechanisms in diabetic vascular complications. Inhibition of HDAC activity by NaB increases the occupancy of AHR and P300
at nfe2l2 promoter to promote the transcriptional activation of nfe2l2, thus protecting against diabetic arterial injuries. miR-24 stimulates the NRF2/HO-1 signaling
pathway to prevent oxidative stress induced by diabetic arterial injuries. miR-200a regulates the Keap1/NRF2 axis to prevent inflammation, thus improving diabetic
BBB damage. The lncRNA MEG3 inhibits DR-induced apoptosis via downregulating the miR-93/NRF2 pathway. Histone methylation of the Keap1 promoter region
increases Keap1 expression and subsequently inhibits the activity of NRF2 to aggravate oxidative stress in DR. C66 upregulates NRF2 expression to protect against
DN-induced oxidative stress by increasing miR-200a expression. The upregulation of miR-200a-3p/141-3p modulates the NRF2 to protect against DN. Omentin-1
downregulates miR-27a and subsequently increases NRF2 expression to inhibit oxidative stress and inflammation in DN. The lncRNA MIAT improves DN by
stimulating NRF2. The lncRNA Blnc1 reduces NRF2 expression to cause oxidative stress and inflammation in DN. NaB, sodium butyrate; HDAC, histone
deacetylase; AHR, aryl hydrocarbon receptor; NRF2, nuclear factor erythroid 2-related factor 2; miR, microRNA; lncRNA MIAT, long non-coding RNA myocardial
infarction-associated transcript; HO-1, heme oxygenase-1; Keap1, Kelch-like ECH-associated protein 1; BBB, blood-brain barrier.

suggested that NRF2-related epigenetic modifications may exert overexpression of lncRNA MEG3 inhibited apoptosis of RPE
antioxidant and anti-inflammatory effects to prevent diabetic cells treated with HG via downregulating miR-93. This study also
BBB injury. Zhao et al. found that the inhibition of HDAC3 indicated that NRF2 is negatively regulated by miR-93 (54). In
activated the miR-200a/Keap1/NRF2 signaling pathway to contrast, knockdown of the lncRNA Sox2OT plays an anti-
attenuate the inflammatory response, thus ameliorating oxidative role via upregulating NRF2/HO-1 signaling in retinal
diabetic-induced BBB permeability (51). Besides, the Keap1/ ganglion cells exposed to HG (55). Besides, histone modifications
NRF2 axis has been reported to be regulated by miR-200a-3p/ at the promoter regions of the retinal genes are important in
141-3p in diabetic renal mesangial cells, suggesting that these regulating NRF2. Mishra et al. investigated the role of epigenetic
miRNAs are involved in reducing oxidative stress and protecting modifications at Keap1 promoter in regulating NRF2 function.
against DN (52). However, whether miR-200a-3P/141-3P can They found that hyperglycemia increased the binding of
regulate the Keap1/NRF2 axis to prevent diabetic BBB stimulating protein-1 (Sp1) at the Keap1 promoter, increased
damage needs to be further explored. monomethylation of H3K4 (H3K4me1), and activated
methyltransferase enzyme Set7/9. Further analysis showed that
Diabetic Retinopathy the inhibition of histone methylation of the Keap1 promoter
DR is one of the most common diabetic microvascular region decreased Keap1 expression and subsequently enhanced
complications, which is a major cause of severe vision loss in the activity of NRF2 to attenuate DR (56). They also investigated
individuals with DM due to retinal microangiopathy (53). the role of epigenetic modifications in the decreased NRF2
ncRNAs have been reported to be associated with a risk of DR, binding at glutamate-cysteine ligase catalytic subunit (Gclc)-
and an increasing number of studies have focused on the effects ARE4 and showed that H3K4me2 at Gclc-ARE4 was elevated,
of ncRNAs on NRF2 in the progression of DR. A recent study H3K4me3 and H3K4me1 as well as NRF2 binding at Gclc-ARE4
showed that expression of the lncRNA MEG3 and NRF2 was were reduced in DM. Histone demethylase (LSD1) siRNA
reduced, but the expression of miR-93 was elevated in blood increased H3K4me1 at Gclc-ARE4 and enhanced NRF2
samples from DR patients as well as in HG-treated human retinal binding at Gclc-ARE4 and Gclc transcripts (57). However, the
pigment epithelium (RPE) and ARPE-19 cells. However, relationship between H3K4me1 at Gclc-ARE4 and NRF2 binding

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Wang(b) et al. NRF2 in Diabetic Complications

at Gclc-ARE4 needs to be further investigated. The above findings anti-cancer properties (65–68). Resveratrol was shown to
provide a novel perspective for the treatment of DR. prevent HG-induced oxidative stress in HepG2 cells via
suppressing methylation of Nfe2l2, which attenuated HG-
Diabetic Nephropathy induced triglyceride accumulation (36). Sulforaphane (SFN),
DN is a complication of type I and type II DM caused by found in cruciferous vegetables like broccoli, bok-choy, and
microvascular changes (58, 59). In recent years, accumulating cabbage, has also been reported to block methylation of the
studies have confirmed that NRF2 prevents DN progression via Nfe2l2 promoter, thereby enhancing its transcriptional activity
epigenetic modifications. Inhibition of HDAC by NaB has been (20, 69–72). For instance, SFN can decrease the protein
proposed to activate Nfe2l2 gene transcription to ameliorate DN expression of DNMT1 and DNMT3a and induce
by enhancing transcription factor binding to the promoter region demethylation of the first 5 CpGs in the Nfe2l2 promoter
of the Nfe2l2 gene (60). Song et al. demonstrated that omentin-1 region. This finding was corroborated by increased mRNA and
can decrease the expression of inflammatory markers interlukin- protein expression of NRF2 and its downstream target gene
8, monocyte chemotactic protein 1, and tumor necrosis factor-a, NQO-1 in TRAMP-C1 cells, suggesting that SFN might protect
and the oxidative stress marker malondialdehyde, as well as against prostate cancer-induced oxidative stress (72). In addition,
elevate antioxidant enzymes catalase and superoxide dismutase luteolin, a flavonoid compound that is isolated from bird’s eye
(SOD). Further mechanistic analysis revealed that omentin-1 can chilli, onions, carrots, and olive oil (73), can enhance DNA
downregulate miR-27a to increase the expression of NRF2 by demethylation of the NFE2L2 promoter to protect against
reducing miR-27a binding at the NRF2 3’ untranslated region oxidative stress in human colorectal cancer HCT116 cells (74).
(UTR) in type II DN (61). Moreover, pelargonidin, fucoxanthin, tanshinone IIA, reserpine,
Another study by Wu et al. indicated that miR-200a is a and delphinidin have been used in the treatment of skin cancer,
pivotal factor that mediates the expression of NRF2 in the while curcumin, g-tocopherol-rich mixture of tocopherols (g-
treatment of DN. They reported that renal expression of NRF2 TmT) and 3,3’-diindolylmethane (DIM) have been proposed to
and miR-200a was downregulated, but the expression of Keap1 prevent prostate cancer; all of these protective effects are
was upregulated in diabetic mice. However, C66 downregulated mediated by decreasing methylation of the Nfe2l2 promoter
Keap1 expression and subsequently upregulated NRF2 (75–82). Therefore, therapeutic strategy targeting the
expression to protect against DN-induced albuminuria, demethylation of the nfe2l2 promoter region may be an
oxidative damage, and fibrosis by increasing miR-200a effective method to attenuate oxidative stress.
expression (62). Opposite with the above finding, Civantos As a potential treatment strategy for many diseases, histone
et al. found that the miR-200a/Keap1/NRF2 pathway was modifications-based therapies have gained significant interest.
diminished following treatment with sitagliptin to ameliorate The protection conferred by HDAC inhibition may be
oxidative stress induced by DN (48). However, more studies associated with the upregulation of histone acetylation at the
regarding these controversial findings are needed to achieve a promoter region of nfe2l2. NaB, a natural short-chain fatty acid, is
more comprehensive understanding. Moreover, aldose reductase an HDAC inhibitor that affects proliferation, differentiation, and
deficiency was shown to upregulate miR-200a-3p/141-3p to apoptosis of cell (83). Dong et al. demonstrated that NaB may
regulate Keap1/NRF2 signaling pathway to protect against DN activate Nfe2l2 at the transcriptional level to ameliorate DN
(52). LncRNAs have also been found to regulate NRF2 in DN. possibly by inhibiting HDAC activity (60). They subsequently
The lncRNA myocardial infarction-associated transcript (MIAT) found that NaB can decrease oxidative stress and inflammatory
has been shown to improve HG-induced renal tubular epithelial response in the aorta. Specifically, NaB suppressed the activity of
injury by stimulating NRF2 (63). To the contrary, the expression HDAC and increased the interaction of AHR and P300 at the
of NRF2 was decreased by the lncRNA Blnc1 in HK-2 cells Nfe2l2 promoter to increase the expression of NRF2, alleviating
exposed to HG (64). Thereby, the regulation of NRF2 by DM-related aortic endothelial dysfunction (41). Additionally,
lncRNAs should be further explored as potential therapeutics corosolic acid, a triterpenoid found in various plants, such as
to reduce the burden of DN. Schisandra chinensis, Lagerstroemia speciosa L., and Weigela
subsessilis (84), is reported to have anti-cancer activity. One
study investigated the effects of corosolic acid on NRF2 via
EPIGENETIC MODIFICATIONS OF NRF2 epigenetic modifications and found that it exerts its antioxidant
BY PHARMACOLOGICAL AGENTS effect by increasing H3K27ac and decreasing H3K27me3 at the
Nfe2l2 promoter region in TRAMP-C1 prostate cells (9). Another
Emerging studies have indicated that aberrant DNA methylation study investigated the effect of the epigenetic regulator Set7/9 in
of nfe2l2 serves as a crucial driving factor in the occurrence and modulating NRF2 expression and found that Set7/9 knockdown
development of various diseases (36). Many antioxidant reduced H3K4me1 enrichment at the promoter region of
compounds have been proposed to regulate nfe2l2 expression NFE2L2, while treatment with two phytochemicals, phenethyl
by modulating DNA methylation at the CpG sites of the isothiocyanate (PEITC) and ursolic acid (UA), elevated the
promoter sequence of nfe2l2. Resveratrol, widely found in enrichment (85). Collectively, the above findings emphasize the
grapes, mulberries, peanuts, and red wine, is a natural phenolic importance of NRF2 agonists and their epigenetic effects on
compound with strong anti-inflammatory, antioxidant, and the Nfe212 promotor in the prevention of multiple diseases.

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Wang(b) et al. NRF2 in Diabetic Complications

TABLE 1 | Pharmacological agents reported to regulate NRF2 signaling epigenetically.

Reference Pharmacological agents Cell/Animal type Epigenetic mechanism

(36) Resveratrol HepG2 cells and C57/BL6 mice decrease methylation of Nfe2l2
(72) SFN TRAMP-C1 cells decrease methylation of Nfe2l2
(76) Curcumin TRAMP-C1 cells decrease methylation of Nfe2l2
(81) g-TmT TRAMP-C1 cells and TRAMP mice decrease methylation of Nfe2l2
(82) DIM TRAMP-C1 cells and TRAMP mice decrease methylation of Nfe2l2
(74) Luteolin HCT116 cells decrease methylation of Nfe2l2
(75) Pelargonidin JB6 P+ cells decrease methylation of Nfe2l2
(77) Fucoxanthin JB6 P+ cells decrease methylation of Nfe2l2
(78) Tanshinone IIA JB6 P+ cells decrease methylation of Nfe2l2
(79) Reserpine JB6 P+ cells decrease methylation of Nfe2l2
(80) Delphinidin JB6 P+ cells decrease methylation of Nfe2l2
(41) NaB ECs and C57BL/6 mice inhibit HDAC activity
(60) NaB C57BL/6 mice inhibit HDAC activity
(9) Corosolic acid TRAMP-C1 cells increase H3K27ac and decrease H3K27me3 at the
promoter region of Nfe2l2
(85) PEITC and UA PCa LNCaP and PC3 cell lines increase H3K4me1 enrichment at the promoter region of
NFE2L2
(61) Omentin-1 NRK-52E, HK-2, HBZY-1 cell lines and C57BLKS/JNju mice decrease miR-101 targeting 3’ UTR of NRF2
(12) CPDT Primary myocardial cells and Wistar rats decrease miR-503 targeting 3’ UTR of NRF2
(62) C66 C57BL/6 mice increase miR-200a targeting 3’UTR of Keap1 to activate
NRF2 signaling
(52) Zopolrestat Mouse mesangial SV40-Mes13 cells and C57BL/6 mice increase miR-200a-3p/141-3p targeting 3’UTR of Keap1
to activate NRF2 signaling

SFN, sulforaphane;g-TmT, g-tocopherol-rich mixture of tocopherols;

DIM, 3,3’-diindolylmethane; NaB, sodium butyrate; PEITC, phenethyl isothiocyanate; UA, ursolic acid; CPDT, phase II enzyme inducer; NRF2, nuclear factor erythroid 2-related factor 2;
HDAC, histone deacetylase; H3K27ac, acetylation of histone H3 lysine 27; H3K27me3, trimethylation of H3K27; H3K4me1, monomethyl H3K4; 3’ UTR, 3’ untranslated region; Keap1,
Kelch-like ECH-associated protein 1; ECs, endothelial cells; miR, microRNA.

NRF2 agonists could confer their protection via targeting acetylation, and regulation of miRNAs and lncRNAs) on DM-
miRNAs. For example, NRF2 agonists could reduce the direct induced cardiac and vascular complications. However, the
effect of miRNAs on NRF2. Song et al. revealed that omentin-1, a literatures focused on DNA methylation of nfe2l2 in the
novel adipocytokine (86), reduced oxidative stress and treatment of DM-related cardiac and vascular diseases are
inflammatory response to improve the deterioration of DN via limited, and the mechanisms by which miRNAs exert their
downregulating the expression of miR-27a, reducing the binding direct effects on NRF2 have been largely lacking. Current
of miR-27a at the 3’ UTR of NRF2, and significantly increasing literatures indicate that NRF2 agonists have anti-cancer effects,
NRF2 expression (61). As a complex enzyme, the phase II but more studies are needed to understand the role of these
enzyme inducer (CPDT) promotes the expression of HO-1 agonists in treating DM-induced cardiac and vascular diseases.
through activating NRF2 to ameliorate DCM. Specifically, In conclusion, this review highlights the importance of the
CPDT treatment was shown to decrease miR-503 expression NRF2-related epigenetic regulation in diabetic cardiac and
and then upregulate the expression of NRF2 (12). However, vascular complications.
miRNAs can also indirectly regulate NRF2. For example, C66
and zopolrestat act on the 3’UTR of Keap1, further impeding
transcriptional activity of Nfe2l2 (52, 62). Thus, treatment
strategy targeting miRNA-related epigenetic modifications of
AUTHOR CONTRIBUTIONS
NRF2 could potentially prevent the progression of various DM- Study concept and design: All authors. Drafting of the manuscript:
related diseases. Pharmacological agents reported to regulate JW (1st author), MX, and JW (3rd author). Critical revision of the
NRF2 signaling epigenetically have been summarized in Table 1. manuscript for important intellectual content: JG, YG, and YT.
Obtained the funding: JG, JZ, and SW. All authors contributed to
the article and approved the submitted version.
CONCLUSION
Epigenetic regulation plays a crucial role in DM-related cardiac FUNDING
and vascular complications. NRF2-related epigenetic
modifications have evolved as a novel research direction for This study was supported by Qilu Young Scholar’s Program of
the treatment of multiple diseases. Therefore, this review Shandong University (21330089963007), National Natural
highlights the effects of NRF2-associated epigenetic Science Foundation of China (81700329, 81770375), and Jilin
mechanisms (DNA methylation, histone methylation and Science and Technology Department (20200801061GH).

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Wang(b) et al. NRF2 in Diabetic Complications

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Conflict of Interest: The authors declare that the research was conducted in the
Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2
absence of any commercial or financial relationships that could be construed as a
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potential conflict of interest.
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Frontiers in Endocrinology | www.frontiersin.org 10 June 2021 | Volume 12 | Article 598005