Hypertensive epigenetics: from DNA methylation to microRNAs



The major epigenetic features of mammalian cells include DNA methylation, posttranslational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (microRNAs (miRNAs)). An important aspect of epigenetic mechanisms is that they are potentially reversible and may be influenced by nutritional–environmental factors and through gene–environment interactions. Studies on epigenetic modulations could help us understand the mechanisms involved in essential hypertension and further prevent it’s progress. This review is focused on new knowledge on the role of epigenetics, from DNA methylation to miRNAs, in essential hypertension.


Essential hypertension is a disease that develops due to complex interactions of susceptibility genes and environmental factors.1 It is estimated that the overall prevalence of hypertension appears to be around 30%–45% of the general population, with a steep increase with aging.2 The number of adults with hypertension in 2025 is predicted to increase by ~60% to a total of 1.56 billion, particularly projected in economically developing countries.3 As we know, essential hypertension is a significant risk factor for coronary artery disease, stroke and kidney disease.4, 5 Many pathophysiologic factors have been implicated in the genesis of essential hypertension such as increased sympathetic nervous system activity, overproduction of sodium retention hormones and increased or inappropriate renin secretion.6

Improved techniques of genetic analysis, especially genome-wide linkage analysis, have enabled deep search for genes. Most promising findings suggest that there are many genetic loci, each with small effects on blood pressure in the general population.7 Many genes of small effect, which display effect modification in the presence of some environmental factors, are responsible for the etiology of human hypertension.8 However, the genetic contribution to blood pressure variation among individuals is estimated to range from 30% to 50%.8 Epigenetic regulation, which can alter gene expression without changing the nucleotide base sequence of gene, may result from environment–gene interactions.9 Epigenetics is emerging as one of important regulators of transcription of specific genes involved in the pathogenesis of essential hypertension.

Definition of epigenetics

Epigenetic phenomena are defined as heritable mechanisms that establish and maintain mitotically stable patterns of gene expression without modifying the base sequence of DNA.10 The field can be broadly categorized into three areas: DNA base modifications (including cytosine methylation and cytosine hydroxymethylation), posttranslational modifications of histone proteins and RNA-based mechanisms that operate in the nucleus, which collectively enable the cell to respond quickly to environment changes (Figure 1).11, 12

Figure 1

The three areas of epigenetics: DNA base modifications (including DNA methylation and DNA hydroxymethylation), histone modification and RNA-based mechanisms (including long non-coding RNAs and short RNAs).

Gene-specific DNA methylation and essential hypertension

DNA methylation is a covalent modification in which the 5′-position of cytosine is methylated in a reaction catalyzed by DNA methyltransferases with S-adenosyl-methionine as the methyl donor.13 In mammals, this modification occurs exclusively at the C5 position of cytosine residues (5-methylcytosine) and predominantly in the context of CpG dinucleotides.14 However, non-CpG methylation in adult mammalian tissues, such as CpA, CpT and CpNpG sites, has been observed.11, 15 The main function of DNA methylation is to modulate the expression of the genetic information, by modifying the accessibility of DNA to the transcriptional machinery.10

HSD11B2 gene methylation

The HSD11B2 gene, encoding the kidney isoenzyme 11β-hydroxysteroid dehydrogenase, is a candidate for essential hypertension.16 The enzyme 11βHSD type 2 (11βHSD2) isoform binds NAD with high affinity and catalyzes the dehydrogenation of 11β-hydroxyglucocorticoids.17 The absence of 11βHSD2 prevents conversion of cortisol into cortisone, resulting in a rise in intracellular cortisol levels, overstimulation of the mineralocorticoid receptor and excessive sodium reabsorption (Figure 2).18 The activity of the enzyme 11βHSD2 can be indirectly evaluated by measuring urinary tetrahydrocortisol/tetrahydrocortisone ratio; an increase in urinary tetrahydrocortisol/tetrahydrocortisone ratio indicates decreased 11βHSD2 activity.19

Figure 2

Physiological function of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2).

Epigenetic modulation of the HSD11B2 gene has been demonstrated in both rodent model and cultured human cell lines.20 CpG islands covering the promoter and exon 1 of HSD11B2 are found to be densely methylated in tissues and cell lines with low expression.20 Demethylation induced by 5-aza-2′-deoxycytidine and procainamide enhances the transcription and activity of the 11βHSD2 enzyme in human cells in vitro and in rats in vivo.20 Moreover, methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt and nuclear factor 1, diminishes their DNA-binding activity.20 In a human study, the HSD11B2 promoter region has an elevated methylation status in glucocorticoid-treated patients who develop hypertension.21 Furthermore, the higher DNA methylation at HSD11B2 promoter sites parallels a higher urinary tetrahydrocortisol/tetrahydrocortisone ratio.21 These present results suggest DNA methylation is a major mechanism for the regulation of HSD11B2 gene expression by modulating the binding of transcription factors and has a role in the pathogenesis of hypertension.

ACE gene methylation

Two isoforms, somatic and germinal angiotensin-converting enzyme (ACE), are transcribed from two alternate promoters within a single gene termed ace-1.22 Somatic ACE isoform is a key regulator of blood pressure. It catalyzes the conversion of angiotensin I into physiologically active angiotensin II, a substance with potent vasopressive properties, and degrades the vasodilator bradykinin.23, 24 In mice, inhibition of ACE activity reduces angiotensin II levels in blood and tissues.25 In clinical practice, ACE inhibitors are of established benefit for the treatment of hypertension.

Two CpG islands are identified in the human ace-1 gene 3 kb proximal promoter region and their methylation abolishes the luciferase activity of ace-1 promoter/reporter constructs transfected into human liver (HepG2), colon (HT29), microvascular endothelial (HMEC-1) and lung (SUT) cell lines.26 Inhibition of DNA methylation by 5-aza-2′-deoxycytidine stimulates sACE mRNA expression specifically in in vitro cell type and in vivo tissue type.26 5-Aza-2′-deoxycytidine induces an increase (~25 mm Hg) in blood pressure after a single injection in the rat, associated with an elevated sACE expression in the lungs and the liver of treated rats, and a substantial and unexpected decrease of plasma angiotensin II levels.26 In low birth-weight children, DNA methylation status in three CpG sites (nucleotide positions +555, +561 and +563) from the ACE gene promoter is decreased, simultaneously with an increase in the ACE protein activity and high blood pressure levels.27 Furthermore, systolic blood pressure levels and ACE protein activity are inversely correlated with the degree of DNA methylation.27 Epigenetic regulation of ACE gene expression might be crucial in the control of blood pressure through angiotensin II-dependent pathways.

NKCC1 gene methylation

The solute carrier family 12 member 2 (SLC12A2), which is also called Na+-K+-2Cl cotransporter 1 (NKCC1), mediates the symport of sodium, potassium and chloride.28 NKCC1 is expressed in most of the cells including vascular smooth muscle cells (VSMCs), endothelial cells, cardiomyocytes, neurons, glial cells and blood cells.28 Under baseline conditions ([Na+]o>>[Na+]i and [Cl]o2>>[Cl]i2), NKCC provides inwardly directed net ion flux and maintenance of [Cl]i above values predicted by the Nernst equilibrium potential.28 In VSMCs, the contribution of K permeability (PK) to resting membrane potential (Em) is somewhat similar with that of Cl permeability (PCl).29 NKCC-mediated modulation of [Cl]i affects Em-dependent and Em-independent VSMC contraction.30 High-ceiling diuretics, inhibitors of NKCC1, decrease [Cl]i, hyperpolarize VSMCs, attenuate the activation of levo-type Ca2+ channels and reduce smooth muscle contractions.31 NKCC1 has a role in the onset of high blood pressure, via an increased cytosolic chloride accumulation in VSMCs.32

In cultured cells, WNK1 (with-no-lysine 1) is activated by either hyperosmotic stress or hypotonic low Cl conditions.33, 34 SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1) are physiological substrates for WNK1, conditions that stimulate WNK1 activation in cells induces the activation of endogenous SPAK and OSR1.35 CCT domain of SPAK and OSR1 interacts with RFXV motifs on NKCC1 as well as WNK1 and WNK4 with high affinity.36 Wnk1+/− mice exhibit a significant alteration in blood pressure and vasoconstricting responses specific to α1-adrenergic vasoconstrictors in both conductance and resistive arteries.37 WNK1 is a major protein in the vasoconstriction pathway linking α1-adrenergic receptors and its downstream effectors SPAK/OSR1 and NKCC1 (Figure 3).

Figure 3

The WNK-SPAK/OSR1 signaling pathway by which the Na+-K+-2Cl cotransporter 1 (NKCC1) is regulated and affects vascular contraction in essential hypertension.

Lee et al.38 analyzed promoter methylation of the NKCC1 gene (official gene symbol SLC12A2) in male Wistar Kyoto (WKY) and spontaneously hypertensive rat (SHR). They revealed that NKCC1 promoter is hypomethylated in the aorta and hearts of SHR, that is, coincided with upregulation of NKCC1 mRNA and protein compared with WKY.38 Furthermore, the promoter region of NKCC1 in WKY is methylated with age, while that in SHRs remains hypomethylated during postnatal development of hypertension.39 The activity of DNA methyltransferases after development of hypertension is about threefold higher in WKY than SHR, which is in accordance with the methylation status on the NKCC1 promoter of WKY and SHR.39 Phenylephrine-induced vasoconstrictions are significantly attenuated by bumetanide (an inhibitor of NKCC1) in both isolated aortae and second-order mesenteric artery of SHR than those of WKY.38 This declined effect of phenylephrine by bumetanide is partially caused by higher expression of NKCC1 mRNA and protein in SHR.38 These data provide new insights into the epigenetic mechanism of the action of NKCC1 that may contribute to the development of hypertension.

ADD1 gene methylation

ADD1 (α-adducin) gene, a candidate gene for essential hypertension,40 encodes one of adducin subunits and is expressed in most tissues.41 Adducin selectively binds to the spectrin–actin network and recruits additional spectrins to actin filaments.41 The actin-based cytoskeleton interacts with the band 3-anion exchanger, the epithelial Na channels, the Na-K-Cl cotransport and the Na-K ATPase.42 Cells transfected with Milan hypertensive rats adducin have shown a significant increase in Na–K pump activity at Vmax and of Na–K pump units compared with cells carrying the Milan normotensive strain adducin.43 Thus, adducin modulates the surface expression of multiple transporters and ion pumps, and regulates cellular signal transduction and cytoplasmic ion transport.40

An association study with 33 hypertensive patients and 28 age- and gender-matched controls showed that DNA methylation levels are closely correlated among CpG2–5, and ADD1 CpG2–5 methylation levels are significantly associated with essential hypertension.44 However, ADD1 CpG1 methylation level is significantly associated with essential hypertension in females but not in males, and lower levels of ADD1 CpG2–5 methylation is associated with increased risk of essential hypertension in males.44

ADRB1 gene methylation

The sympathetic nervous system has a crucial role in the regulation of blood pressure, mainly through activating α- and β-adrenergic receptors in the effector organs, including the heart, kidney and the blood vessels.45 The β1-adrenoreceptor (ADRB1) gene is one of the hypertension-susceptibility candidates as a pivotal mediator of signal transduction in cardiac, vascular, endocrine and sympathetic adrenal systems.46 The human ADRB1, which mediates the actions of catecholamines in the sympathetic nervous system, is a key cell surface signaling protein expressed in multiple organs and tissues including the heart, kidney, brain and the pineal gland.47

The ADRB1 promoter has many methylated sites.48 According to the animal model experiment, SHRs that had better antihypertensive response to metoprolol showed a lower level of DNA methylation modification and a higher expression of ADRB1 in their myocardial tissues.48 In SHRs, hypomethlation of the ADRB1 promoter is likely to improve the antihypertensive efficacy of metoprolol.48 Thus, the epigenetic molecular mechanism could lead to ADRB1 gene-directed therapy.

αENaC gene methylation

The epithelial sodium channel (ENaC) consists of three homologous subunits α, β and γ, which are encoded by the sodium channel, non-voltage-gated 1α (Scnn1a), β (Scnn1b) and γ (Scnn1G) genes, respectively.49 ENaC is expressed in the apical membrane of salt-absorbing epithelia of kidney, distal colon and lung airways.49 ENaC has a major role in Na+ reabsorption in the distal tubule, and hence the regulation of Na+ balance, extracellular fluid volume and blood pressure.50 Of the three ENaC subunits, αENaC appears to be critical to the overall salt balance. Mice with targeted inactivation of αENaC in the connecting tubule/collecting duct exhibit severe renal salt wasting characteristic of a pseudohypoaldosteronism type I phenotype.51 Aldosterone is a major regulator of epithelial Na+ absorption and acts in large part through ENaC induction in the renal collecting duct.52, 53 In this region, aldosterone administration or hyperaldosteronism induced by a low-Na+ diet increases αENaC gene transcription, without increasing β- or γ-subunit expression.54

A CpG island near the transcription start site of the αENaC promoter is regulated by the control of promoter methylation status (Figure 4). Under basal conditions, cytosine methylation in this region of the αENaC promoter is evident in mIMCD3 cells.55 5-Aza-2′-deoxycytidine-mediated promoter demethylation enhances Sp1 binding to, and transactivation of the αENaC promoter, thus increases αENaC mRNA expression.55 Aldosterone reprograms the methylation status of the R3 subregion of the αENaC promoter from a predominance of 5-methylcytosine under basal conditions to a predominance of 5-hydroxymethylcytosine.55 This change is accompanied by depletion of DNMT3b at this subregion and enhances enrichment of Tet2.55 Aldosterone treatment disperses DNMT3b from the αENaC R3 subregion and recruits Tet2 to convert 5-methylcytosine to 5-hydroxymethylcytosine at this subregion, to contribute to the derepression of αENaC transcription.55 Aldosterone-dependent demethylation of the αENaC promoter also facilitates Sp1 binding to the promoter, to allow further transactivation of the αENaC gene.55

Figure 4

Two epigenetic mechanisms of αENaC for derepression: disruption of Dot1a-mediated histone H3K79 methylation and the targeted demethylation of the αENaC promoter.

Histone modification in essential hypertension

Genomic DNA is compacted in the chromatin, whose basic unit is the nucleosome that is formed by an octamer of histone proteins H2A, H2B, H3 and H4. Posttranslational modifications occurring at residues in N-terminal tail of histone include phosphorylation, sumoylation, biotinylation, acetylation and methylation, and control the dynamics of chromatin to regulate gene expression.56

Acetylation modification

The acetylation/deacetylation balance among most of studies is one of histone-related epigenetic mechanisms, and histone–histone or histone–DNA interplay regulates gene expression.57 Histone H3 is acetylated by histone acetyltransferase at different lysine positions and the site is indicative of different events; for example, acetylation at lysine-14 indicates active transcription of DNA into RNA.58

Acetylation modification in the neurons of area postrema

Melatonin secretion from pineal gland may be disturbed by almost all environmental factors, such as light and temperature.59 Melatonin as an appropriate mediator transfers the environmental information to the area postrema (AP), where the high levels of nuclear melatonin receptors are located.60 The rostral ventrolateral medulla neurons receive excitatory input from AP, which responds to blood and cerebrospinal fluid signals, and provide excitatory output to preganglionic neurons in the intermediolateral cell column of the spinal cord, which provide sympathetic output to target organs.60 Treatment with physiological (nanomolar) concentrations of melatonin for 24 h was reported to increase the acetylation of histone H3 in progenitor cells, augment neurite-like extensions and promote mRNA expression of nestin, a neural stem cell marker.61 Melatonin was also reported to increase the mRNA expression of various other histone acetyltransferase isoforms.61 Environmental stressors affect melatonin secretion and cause epigenetic modifications in the neurons of AP, shifting the blood pressure set-point signal of the AP to a higher pressure.60 This signal may then operate through efferent projections to key medullary sympathetic nuclei in the rostral ventrolateral medulla, thereby increasing brainstem sympathetic outflow and explaining the long-term alterations in sympathetic activity associated with essential hypertension.60, 62 The axis of pineal gland–AP–rostral ventrolateral medulla participates in adaptive responses to environmental and internal stressors and the pathogenesis of essential hypertension.

Acetylation modification at WNK4 promoter region

WNK4 is a member of the serine–threonine protein kinase family. Human WNK4 (hWNK4) expresses mainly in the kidney and partly in polarized epithelia.63 It acts as a multifunctional regulator of diverse ion transporters, including NaCl cotransporter and renal outer medullary K+ channel, and can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.64 Therefore, it may be involved in pathophysiological processes of fluid and electrolyte perturbations and hypertension.63

It has been demonstrated that glucocorticoid downregulates hWNK4 expression through the negative glucocorticoid responsive elements.65 The β2-adrenergic receptor stimulation leads to cyclic adenosine monophosphate-dependent inhibition of histone deacetylase-8 activity in the kidney and increases histone acetylation in the WNK4 promoter region, resulting in transcriptional modulation dependent on glucocorticoid receptors binding to a negative glucocorticoid responsive element in this region.66 Trichostatin A, a histone deacetylase inhibitor, upregulates hWNK4 mRNA and protein expression within the hWNK4 promoter in HEK293 cells.67 In rat models, salt loading suppresses renal WNK4 expression, activates Na+-Cl cotransporter and induces salt-dependent hypertension.66 These findings suggest epigenetic modulation of WNK4 transcription in the development of salt-sensitive hypertension.

Histone modification at αENaC promoter region

Dot1a (disruptor of telomeric silencing alternative splice variant ‘a’) is a lysine methyltransferase that methylates the histone H3K79 site of nucleosomes and disrupts the process of silencing genes located in the telomeric regions of chromosomes during DNA repair for maintaining telomere length.49 Af9, the fused mixed-lineage leukemia and acute lymphoblastic leukemia gene mapped to chromosome 9 (Af9), produces a sequence-specific DNA-binding protein that binds to Dot1a.49

Af9, a putative transcription factor, physically and functionally interacts with Dot1a to form a nuclear repressor complex, which, via direct or indirect binding to specific sites in the αENaC promoter, regulates histone H3K79 methylation at these sites and represses basal transcription of αENaC.68 Aldosterone downregulates the Dot1a–AF9 complex, at least in part by inhibiting Dot1 and AF9 expression, leading to targeted histone H3K79 hypomethylation and transcriptional activation of αENaC.68 Furthermore, Af9 has been identified as a physiologic target for Sgk1 (serum- and glucocorticoid-induced kinase-1) phosphorylation, and Sgk1 as a novel component and negative regulator of the Dot1a-Af9 complex.53 Aldosterone not only downregulates the abundance of the components of the Dot1a-Af9 complex but also (via Sgk1-mediated phosphorylation of Af9) weakens their interaction, leading to targeted histone H3K79 hypomethylation at the αENaC promoter and derepression of αENaC transcription.53 The Dot1a-Af9 pathway is thus likely to influence the expression of this gene regulating sodium transport (permeability), contributing to renal fibrosis and genetic predilections for salt-sensitive hypertension.69 AF17 competes with AF9 for interaction with Dot1a and antagonizes the epigenetic repressor effects of Dot1a-AF9 on αENaC transcription, and augments αENaC-mediated Na+ transport under basal conditions.70 The positive regulatory effect of AF17 on αENaC transcription appears to involve, at least in part, enhances nuclear export of Dot1a to the cytoplasm, the resulting reduction in nuclear Dot1a expression leads to H3K79 hypomethylation and de-repression of αENaC transcription.70

Aldosterone-induced αENaC transcription includes transactivation mediated by the binding of the liganded mineralocorticoid receptor to glucocorticoid responsive elements and recruitment of Sp1 to its cis-element, and at least two epigenetic mechanisms for derepression: disruption of Dot1a-mediated histone H3K79 methylation and the targeted demethylation of the αENaC promoter (Figure 4).55

MicroRNAs and essential hypertension

microRNAs (miRNAs) are endogenously produced non-coding RNA molecules, ~22 nucleotides long, that have a ubiquitous and important role in regulating protein expression. At least 30% of human genes are thought to be regulated by miRNAs, one of the classes of small RNA.71 The human genome contains genes coding at least 2588 mature human miRNAs. Some miRNA genes are located in introns of protein-coding genes or form transcriptional unit with adjacent protein-coding genes.72 Some miRNA genes are located close to each other in the genome and form miRNA cluster.72 In addition, some miRNAs, such as miR-149 and miR-29b, are encoded by multiple copies of genes.72

Similar to mRNA, miRNAs are transcribed from endogenous miRNA genes as primary transcript (pri-miRNA), containing 65- to 70-nucleotide stem-loop structure.73, 74, 75 The hairpin structure is excised in the nucleus by the Drosha-DGCR8 complex to yield a precursor miRNA.73, 74, 75 Precursor miRNA is transported by exportin-5 into the cytosol, where Dicer cleaves the Precursor miRNA, producing a short double-stranded RNA fragment called miRNA:miRNA duplex.73, 74, 75 The duplex is successively incorporated into the RNA-induced silencing complex.10 Within the RNA-induced silencing complex the miRNA duplex is unwound and split into two single strands; the mature miRNA single strand is retained in the complex, determining the formation of miRNA-induced silencing complex, while the other strand is lost (Figure 5).10 The seed sequence of a miRNA in these protein complexes pairs with complementary sites in the 3′-untranslated region (3′UTR) of target mRNAs through RNA–RNA base pairing that involves not only the Watson–Crick A:U and G:C pairs but also the G:U pair.76 In the canonical pathway, base pairing is recognized between the 2 and 8 nucleotide seed sequence of the miRNA and the mRNA 3′UTR.77 In the non-canonical pathway, miRNA binding to its mRNA targets relies less on seed sequence homology and more on complementarity in coding regions or the 5′UTR of the target transcript.78

Figure 5

The biogenesis of miRNAs.

In general, miRNAs bind to the 3′UTR of their target mRNA and reduce the abundance of target proteins by repression of target mRNA translation and removal of mRNA poly (A) tail (that is, deadenylation), resulting in mRNA degradation.74 miRNAs emerge recently on the scene of epigenetics as factors of important mechanisms capable of modulating and controlling the expression of genes. Key miRNAs regulate the expression levels of hundreds of genes simultaneously, and many types of miRNAs regulate their targets cooperatively.79

AGT-regulated miR-584 and miR-31

Human angiotensinogen (AGT) gene, which is associated with essential hypertension in Caucasians, Japanese and Asian Indian subjects, has a C/A polymorphism at +11525 (rs7079) located in the 3′UTR.80 Both in HEK293 cells and Hep3B cells, transfection of miR-31 or miR-584 downregulates the luciferase activity of reporter construct containing only the 11525C allele and not the 11525A allele.80 Moreover, anti-miRNAs relieve the miR-584- and miR-31-induced downregulation of the luciferase gene-containing 11525C allele of the 3′UTR of hAGT gene.80 In addition, transfection of either miR-31 or miR-584 also reduces the hAGT mRNA/protein level in Hep3B cells.80 Owing to decreased binding of miR-584 and miR-31, human subjects having the 11525A allele may have increased hAGT expression compared with human subjects with the 11525C allele (Table 1).80 This may lead to increased plasma or tissue hAGT levels, ultimately resulting in increased blood pressure in human subjects with the 11525A allele compared with human subjects with the 11525C allele.80

Table 1 RAS components and target miRNAs

REN-binding miR-181a and miR-663

The transcriptome-wide study of differential expression of mRNAs and miRNAs in the kidney in human hypertension showed that several of the mRNAs identified have miRNA targets in their 3′UTR.81 Functional experiments in cultured kidney cells showed that two selected miRNA, miR-181a and miR-663, may exert posttranscriptional control of renin (REN), apolipoprotein E (APOE) and apoptosis-inducing factor mitochondrion-associated 1 (AIFM1) mRNAs via their 3′UTR.81 In human hypertension, endogenous REN gene is overexpressed and the expression of miR-181a and miR-663 is reduced.81 REN mRNA may be regulated via binding of miR-181a and miR-663 to its 3′UTR (Table 1).81

miRNA as biomarkers


miR-483-3p is one of the 22 VSMC-specific miRNAs, whose expression is decreased on chronic angiontensin I receptor activation.82 This miRNA is encoded within intron 2 of the insulin-like grow factor 2 (IGF2) gene in humans and rodents.82 IGF2 gene is known to be regulated by angiontensin II signaling and in turn IGF2 signaling affects renin–angiotensin system (RAS) functions.82

The miR-483-p targets of the components of RAS were predicted using multiple commonly used miRNA target prediction algorithms (Target-Scan, PITA, DIANA and MicroCosm). Prediction results showed that 3′UTRs of AGT, angiotensin-converting enzyme-1 (ACE-1), angiotensin-converting enzyme-2 (ACE-2) and angiontensin II receptor (AT2R) each contain a single site in the genes’ 3′UTR for miR-483-3p.82 Cotransfection experiments clearly demonstrated that miR-483-3p can effectively initiate the RNA interference process on the target 3′UTRs of AGT, ACE-1, ACE-2 and AT2R, suggesting that this miRNA could be a global regulator of tissue RAS.82 In the miR-483-3p-expressing RASMC (human aortic smooth muscle cells)–angiontensin I receptor cells, protein levels of these miR-483-3p targets consistently decrease.82 Decreased levels of AGT and ACE-1 in these cells can be rescued by transfection with an antagomir (one of miRNA inhibitors) to miR-483-3p.82 In the presence of miR-483-3p, there is no change in AGT, ACE-1, ACE-2 and AT2R transcripts.82 Thereby, miR-483-3p does not induce degradation of transcripts of these target genes, but acts on posttranscriptional levels of these genes.82 Four different RAS components could be as targets of the angiontensin I receptor -regulated miR-483-3p (Table 1).82 Thus, miRNA regulation by angiontensin II to affect cellular signaling is a novel aspect of RAS biology, which may lead to discovery of potential candidate prognostic markers and therapeutic targets.82


hWNK4 3′UTR is highly conserved and functions as an enhancer in HEK293 and BGC823 cells, no matter whether under a heterologous or a homologous promoter.63 The enhancer and promoter of the hWNK4 gene interact physically, with the intervening DNA looped out in hWNK4-expressing HEK293 cells, but not in non-hWNK4-expressing Hela cells.63 The transcriptional factor GATA-1 and it’s motif could be a part of the bridge between the promoter and 3′UTR of hWNK4.63 After overexpressing miR-296, the level of hWNK4 protein decreases but not the mRNA. Thus, miR-296 targets on the hWNK4 3′UTR to downregulate gene expression at the posttranscriptional level.63 A coordinated modulation by miR-296 and cofactors may be attributed to hWNK4 physiopathological function and provide a novel therapeutic clue for hypertension.63

miR-9 and miR-126

A recent study in mice has revealed that the nuclear factor of activated T cells c3 and myocardia, which participate in the aldosterone-induced hypertrophic pathway, can both be targeted by miR-9.83 miR-126, which is one of the most abundant miRNAs in endothelial cells, has been found to regulate angiogenic signaling and vascular integrity.84 Based mainly on experimental animal studies, it has been suggested that miR-9 and miR-126 could have a role in human hypertension.85

To confirm their involvement in the pathophysiology of hypertension in humans, 60 patients with hypertension and 29 healthy volunteers were enrolled in this study.86 The expression levels of miR-9 and miR-126 are lower in hypertensive patients than those in healthy controls.86 miR-9 expression levels in peripheral blood mononuclear cells are positively correlated with left ventricular mass index in patients with essential hypertension.86 Administration of miR-9 mimic (double-stranded RNA oligonucleotide) could reverse the hypertrophic response induced by isoproterenol and aldosterone in cellular model.83 Examination of miR-9 and miR-126 expression levels in essential hypertensive patients in relation to 24-h ambulatory blood pressure monitoring parameters revealed significant positive correlations with the 24-h mean pulse pressure.86 These studies indicate that miR-9 and miR-126 may have the potential to be used as prognostic biomarkers and possibly as therapeutic targets in essential hypertension.86

miR-145, miR-132 and miR-212

Recent studies have also found that miR-145 is significantly more expressed in atherosclerotic plaques of hypertensive patients than in plaques from the control patients.87 A post-hoc analysis showed that treatment with angiotensin II receptor blocker is associated with higher levels of miR-145, whereas treatment with ACE inhibitors is associated with lower levels of miR-145, although these data do not show any statistical significance (P=0.06) probably due to the limited sample size (n=22).87 Plasma levels of circulating miR-132 and miR-212 are highly elevated in the heart, aortic wall and the kidney in hypertensive rats, following chronic infusion of angiotensin II,88 whereas these two miRNAs levels are significantly decreased in human arteries from bypass-operated patients treated with angiotensin II receptor blockers, suggesting that circulating miR-132 and miR-212 are involved in angiotensin II-induced hypertension and might be used for therapeutic targets during hypertension management.89


Epigenetic studies on hypertension should be focused, because not only there is an increasing prevalence with hypertension but also hypertension is a major modifiable risk factor for heart disease, kidney disease and stroke. Epigenetic events, differently from genetic sequence, are potentially reversible through their interface with environmental and nutritional factors. A proven effective intervention is lifestyle changes, including weight loss, reduced intake of dietary sodium, low alcohol of consumption, potassium supplementation, modification of eating habits and increased physical activity.4 Epigenetic pathways offer a new perspective in gene regulation. With further research, epigenetics might make a significant contribution for preventive and therapeutic approaches for essential hypertension.


  1. 1

    Pausova Z, Tremblay J, Hamet P . Gene-environment interactions in hypertension. Curr Hypertens Rep 1999; 1 (1): 42–50.

    CAS  Article  Google Scholar 

  2. 2

    Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M et al. ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34 (28): 2159–2219.

    Article  Google Scholar 

  3. 3

    Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J . Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365 (9455): 217–223.

    Article  Google Scholar 

  4. 4

    Whelton PK, He J, Appel LJ, Cutler JA, Havas S, Kotchen TA et al. Primary prevention of hypertension: clinical and public health advisory from The National High Blood Pressure Education Program. JAMA 2002; 288 (15): 1882–1888.

    Article  Google Scholar 

  5. 5

    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J et al. evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014 311 (5): 507–520.

  6. 6

    Oparil S, Zaman MA, Calhoun DA . Pathogenesis of hypertension. Ann Intern Med 2003; 139 (9): 761–776.

    CAS  Article  Google Scholar 

  7. 7

    Ehret GB . Genome-wide association studies: contribution of genomics to understanding blood pressure and essential hypertension. Curr Hypertens Rep 2010; 12 (1): 17–25.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Kunes J, Zicha J . The interaction of genetic and environmental factors in the etiology of hypertension. Physiol Res 2009; 58 (Suppl 2): S33–S41.

    Google Scholar 

  9. 9

    Millis RM . Epigenetics and hypertension. Curr Hypertens Rep 2011; 13 (1): 21–28.

    CAS  Article  Google Scholar 

  10. 10

    Udali S, Guarini P, Moruzzi S, Choi SW, Friso S . Cardiovascular epigenetics: from DNA methylation to microRNAs. Mol Aspects Med 2013; 34 (4): 883–901.

    CAS  Article  Google Scholar 

  11. 11

    Webster AL, Yan MS, Marsden PA . Epigenetics and cardiovascular disease. Can J Cardiol 2013; 29 (1): 46–57.

    Article  Google Scholar 

  12. 12

    Ordovás JM, Smith CE . Epigenetics and cardiovascular disease. Nat Rev Cardiol 2010; 7 (9): 510–519.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13

    Miranda TB, Jones PA . DNA methylation: the nuts and bolts of repression. J Cell Physiol 2007; 213 (2): 384–390.

    CAS  Article  Google Scholar 

  14. 14

    Rottach A, Leonhardt H, Spada F . DNA methylation-mediated epigenetic control. J Cell Biochem 2009; 108 (1): 43–51.

    CAS  Article  Google Scholar 

  15. 15

    Yan J, Zierath JR, Barrès R . Evidence for non-CpG methylation in mammals. Exp Cell Res 2011; 317 (18): 2555–2561.

    CAS  Article  Google Scholar 

  16. 16

    Mariniello B, Ronconi V, Sardu C, Pagliericcio A, Galletti F, Strazzullo P et al. Analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension. Am J Hypertens 2005; 18 (8): 1091–1098.

    CAS  Article  Google Scholar 

  17. 17

    Frey FJ, Odermatt A, Frey BM . Glucocorticoid-mediated mineralocorticoid receptor activation and hypertension. Curr Opin Nephrol Hypertens 2004; 13 (4): 451–458.

    CAS  Article  Google Scholar 

  18. 18

    Ferrari P . The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension. Biochim Biophys Acta 2010; 1802 (12): 1178–1187.

    CAS  Article  Google Scholar 

  19. 19

    Campino C, Carvajal CA, Cornejo J, San Martín B, Olivieri O, Guidi G et al. 11β-Hydroxysteroid dehydrogenase type-2 and type-1 (11β-HSD2 and 11β-HSD1) and 5β-reductase activities in the pathogenia of essential hypertension. Endocrine 2010; 37 (1): 106–114.

    CAS  Article  Google Scholar 

  20. 20

    Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM . Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression. J Clin Invest 2004; 114 (8): 1146–1157.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21

    Friso S, Pizzolo F, Choi SW, Guarini P, Castagna A, Ravagnani V et al. Epigenetic control of 11 beta-hydroxysteroid dehydrogenase 2 gene promoter is related to human hypertension. Atherosclerosis 2008; 199 (2): 323–327.

    CAS  Article  Google Scholar 

  22. 22

    Howard TE, Shai SY, Langford KG, Martin BM, Bernstein KE . Transcription of testicular angiotensin-converting enzyme (ACE) is initiated within the 12th intron of the somatic ACE gene. Mol Cell Biol 1990; 10 (8): 4294–4302.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23

    Andrade MC, Quinto BM, Carmona AK, Ribas OS, Boim MA, Schor N et al. Purification and characterization of angiotensin I-converting enzymes from mesangial cells in culture. J Hypertens 1998; 16 (12 Pt 2): 2063–2074.

    CAS  Article  Google Scholar 

  24. 24

    Duncan AM, Burrell LM, Kladis A, Campbell DJ . Effects of angiotensin-converting enzyme inhibition on angiotensin and bradykinin peptides in rats with myocardial infarction. J Cardiovasc Pharmacol 1996; 28 (6): 746–754.

    CAS  Article  Google Scholar 

  25. 25

    Campbell DJ, Alexiou T, Xiao HD, Fuchs S, McKinley MJ, Corvol P et al. Effect of reduced angiotensin-converting enzyme gene expression and angiotensin-converting enzyme inhibition on angiotensin and bradykinin peptide levels in mice. Hypertension 2004; 43 (4): 854–859.

    CAS  Article  Google Scholar 

  26. 26

    Riviere G, Lienhard D, Andrieu T, Vieau D, Frey BM, Frey FJ . Epigenetic regulation of somatic angiotensin-converting enzyme by DNA methylation and histone acetylation. Epigenetics 2011; 6 (4): 478–489.

    CAS  Article  Google Scholar 

  27. 27

    Rangel M, dos Santos JC, Ortiz PH, Hirata M, Jasiulionis MG, Araujo RC et al. Modification of epigenetic patterns in low birth weight children: importance of hypomethylation of the ACE gene promoter. PLoS ONE 2014; 9 (8): e106138.

    PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Gamba G . Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 2005; 85 (2): 423–493.

    CAS  Article  Google Scholar 

  29. 29

    Chipperfield AR, Harper AA . Chloride in smooth muscle. Prog Biophys Mol Biol 2000; 74 (3-5): 175–221.

    CAS  Article  Google Scholar 

  30. 30

    Orlov SN, Tremblay J, Hamet P . NKCC1 and hypertension: a novel therapeutic target involved in the regulation of vascular tone and renal function. Curr Opin Nephrol Hypertens 2010; 19 (2): 163–168.

    CAS  Article  Google Scholar 

  31. 31

    Anfinogenova YJ, Baskakov MB, Kovalev IV, Kilin AA, Dulin NO, Orlov SN . Cell-volume-dependent vascular smooth muscle contraction: role of Na+, K+, 2Cl− cotransport, intracellular Cl- and L-type Ca2+ channels. Pflugers Arch 2004; 449 (1): 42–55.

    CAS  Article  Google Scholar 

  32. 32

    Giménez I . Molecular mechanisms and regulation of furosemide-sensitive Na-K-Cl cotransporters. Curr Opin Nephrol Hypertens 2006; 15 (5): 517–523.

    Article  Google Scholar 

  33. 33

    Moriguchi T, Urushiyama S, Hisamoto N, Iemura S, Uchida S, Natsume T et al. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. J Biol Chem 2005; 280 (52): 42685–42693.

    CAS  Article  Google Scholar 

  34. 34

    Zagórska A, Pozo-Guisado E, Boudeau J, Vitari AC, Rafiqi FH, Thastrup J et al. Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. J Cell Biol 2007; 176 (1): 89–100.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35

    Richardson C, Alessi DR . The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway. J Cell Sci 2008; 121 (Pt 20): 3293–3304.

    CAS  Article  Google Scholar 

  36. 36

    Vitari AC, Thastrup J, Rafiqi FH, Deak M, Morrice NA, Karlsson HK et al. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Biochem J 2006; 397 (1): 223–231.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Bergaya S, Faure S, Baudrie V, Rio M, Escoubet B, Bonnin P et al. WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice. Hypertension 2011; 58 (3): 439–445.

    CAS  Article  Google Scholar 

  38. 38

    Lee HA, Baek I, Seok YM, Yang E, Cho HM, Lee DY et al. Promoter hypomethylation upregulates Na+-K+-2Cl− cotransporter 1 in spontaneously hypertensive rats. Biochem Biophys Res Commun 2010; 396 (2): 252–257.

    CAS  Article  Google Scholar 

  39. 39

    Cho HM, Lee HA, Kim HY, Han HS, Kim IK . Expression of Na+-K+ −2Cl− cotransporter 1 is epigenetically regulated during postnatal development of hypertension. Am J Hypertens 2011; 24 (12): 1286–1293.

    CAS  Article  Google Scholar 

  40. 40

    Casari G, Barlassina C, Cusi D, Zagato L, Muirhead R, Righetti M et al. Association of the alpha-adducin locus with essential hypertension. Hypertension 1995; 25 (3): 320–326.

    CAS  Article  Google Scholar 

  41. 41

    Matsuoka Y, Li X, Bennett V . Adducin: structure, function and regulation. Cell Mol Life Sci 2000; 57 (6): 884–895.

    CAS  Article  Google Scholar 

  42. 42

    Manunta P, Barlassina C, Bianchi G . Adducin in essential hypertension. FEBS Lett 1998; 430 (1–2): 41–44.

    CAS  Article  Google Scholar 

  43. 43

    Tripodi G, Valtorta F, Torielli L, Chieregatti E, Salardi S, Trusolino L et al. Hypertension-associated point mutations in the adducin alpha and beta subunits affect actin cytoskeleton and ion transport. J Clin Invest 1996; 97 (12): 2815–2822.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Zhang LN, Liu PP, Wang L, Yuan F, Xu L, Xin Y et al. Lower ADD1 gene promoter DNA methylation increases the risk of essential hypertension. PLoS ONE 2013; 8 (5): e63455.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45

    Zhang YC, Bui JD, Shen L, Phillips MI . Antisense inhibition of beta(1)-adrenergic receptor mRNA in a single dose produces a profound and prolonged reduction in high blood pressure in spontaneously hypertensive rats. Circulation 2000; 101 (6): 682–688.

    CAS  Article  Google Scholar 

  46. 46

    Kong H, Li X, Zhang S, Guo S, Niu W . The β1-adrenoreceptor gene Arg389Gly and Ser49Gly polymorphisms and hypertension: a meta-analysis. Mol Biol Rep 2013; 40 (6): 4047–4053.

    CAS  Article  Google Scholar 

  47. 47

    Wang H, Liu J, Liu K, Liu Y, Wang Z, Lou Y et al. β1-adrenoceptor gene Arg389Gly polymorphism and essential hypertension risk in general population: a meta-analysis. Mol Biol Rep 2013; 40 (6): 4055–4063.

    CAS  Article  Google Scholar 

  48. 48

    Jiang Q, Yuan H, Xing X, Liu J, Huang Z, Du X . Methylation of adrenergic β1 receptor is a potential epigenetic mechanism controlling antihypertensive response to metoprolol. Indian J Biochem Biophys 2011; 48 (5): 301–307.

    CAS  Google Scholar 

  49. 49

    Zhang D, Yu ZY, Cruz P, Kong Q, Li S, Kone BC . Epigenetics and the control of epithelial sodium channel expression in collecting duct. Kidney Int 2009; 75 (3): 260–267.

    CAS  Article  Google Scholar 

  50. 50

    Bhalla V, Hallows KR . Mechanisms of ENaC regulation and clinical implications. J Am Soc Nephrol 2008; 19 (10): 1845–1854.

    CAS  Article  Google Scholar 

  51. 51

    Christensen BM, Perrier R, Wang Q, Zuber AM, Maillard M, Mordasini D et al. Sodium and potassium balance depends on αENaC expression in connecting tubule. J Am Soc Nephrol 2010; 21 (11): 1942–1951.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Thomas CP, Itani OA . New insights into epithelial sodium channel function in the kidney: site of action, regulation by ubiquitin ligases, serum- and glucocorticoid-inducible kinase and proteolysis. Curr Opin Nephrol Hypertens 2004; 13 (5): 541–548.

    CAS  Article  Google Scholar 

  53. 53

    Zhang W, Xia X, Reisenauer MR, Rieg T, Lang F, Kuhl D et al. Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na+ channel alpha. J Clin Invest 2007; 117 (3): 773–783.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Stokes JB, Sigmund RD . Regulation of rENaC mRNA by dietary NaCl and steroids: organ, tissue, and steroid heterogeneity. Am J Physiol 1998; 274 (6 Pt 1): C1699–C1707.

    CAS  Article  Google Scholar 

  55. 55

    Yu Z, Kong Q, Kone BC . Aldosterone reprograms promoter methylation to regulate αENaC transcription in the collecting duct. Am J Physiol Renal Physiol 2013; 305 (7): F1006–F1013.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56

    Margueron R, Reinberg D . Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet 2010; 11 (4): 285–296.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Goldberg AD, Allis CD, Bernstein E . Epigenetics: a landscape takes shape. Cell 2007; 128 (4): 635–638.

    CAS  Article  Google Scholar 

  58. 58

    Kang TJ, Yuzawa S, Suga H . Expression of histone H3 tails with combinatorial lysine modifications under the reprogrammed genetic code for the investigation on epigenetic markers. Chem Biol 2008; 15 (11): 1166–1174.

    CAS  Article  Google Scholar 

  59. 59

    Woldańska-Okońska M, Czernicki J . [Biological effects produced by the influence of low frequency electromagnetic fields on hormone secretion]. Przegl Lek 2003; 60 (10): 657–662.

    Google Scholar 

  60. 60

    Irmak MK, Sizlan A . Essential hypertension seems to result from melatonin-induced epigenetic modifications in area postrema. Med Hypotheses 2006; 66 (5): 1000–1007.

    CAS  Article  Google Scholar 

  61. 61

    Sharma R, Ottenhof T, Rzeczkowska PA, Niles LP . Epigenetic targets for melatonin: induction of histone H3 hyperacetylation and gene expression in C17.2 neural stem cells. J Pineal Res 2008; 45 (3): 277–284.

    CAS  Article  Google Scholar 

  62. 62

    Morimoto S, Sasaki S, Itoh H, Nakata T, Takeda K, Nakagawa M et al. Sympathetic activation and contribution of genetic factors in hypertension with neurovascular compression of the rostral ventrolateral medulla. J Hypertens 1999; 17 (11): 1577–1582.

    CAS  Article  Google Scholar 

  63. 63

    Mao J, Li C, Zhang Y, Li Y, Zhao Y . Human with-no-lysine kinase-4 3′-UTR acting as the enhancer and being targeted by miR-296. Int J Biochem Cell Biol 2010; 42 (9): 1536–1543.

    CAS  Article  Google Scholar 

  64. 64

    Kahle KT, Wilson FH, Leng Q, Lalioti MD, O'Connell AD, Dong K et al. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat Genet 2003; 35 (4): 372–376.

    CAS  Article  Google Scholar 

  65. 65

    Nguyen Dinh Cat A, Ouvrard-Pascaud A, Tronche F, Clemessy M, Gonzalez-Nunez D, Farman N et al. Conditional transgenic mice for studying the role of the glucocorticoid receptor in the renal collecting duct. Endocrinology 2009; 150 (5): 2202–2210.

    Article  CAS  Google Scholar 

  66. 66

    Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F et al. Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med 2011; 17 (5): 573–580.

    CAS  Article  Google Scholar 

  67. 67

    Li M, Zhao Y, Li Y, Li C, Chen F, Mao J et al. Upregulation of human with-no-lysine kinase-4 gene expression by GATA-1 acetylation. Int J Biochem Cell Biol 2009; 41 (4): 872–878.

    CAS  Article  Google Scholar 

  68. 68

    Zhang W, Xia X, Reisenauer MR, Hemenway CS, Kone BC . Dot1a-AF9 complex mediates histone H3 Lys-79 hypermethylation and repression of ENaCalpha in an aldosterone-sensitive manner. J Biol Chem 2006; 281 (26): 18059–18068.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Lee JY, Prineas RJ, Eaton JW . Heritability of erythrocyte sodium permeability: a possible genetic marker for hypertension. Ann Clin Lab Sci 2009; 39 (3): 241–250.

    Google Scholar 

  70. 70

    Reisenauer MR, Anderson M, Huang L, Zhang Z, Zhou Q, Kone BC et al. AF17 competes with AF9 for binding to Dot1a to up-regulate transcription of epithelial Na+ channel alpha. J Biol Chem 2009; 284 (51): 35659–35669.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Lewis BP, Burge CB, Bartel DP . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120 (1): 15–20.

    CAS  Article  Google Scholar 

  72. 72

    Rodriguez A, Griffiths-Jones S, Ashurst JL, Bradley A . Identification of mammalian microRNA host genes and transcription units. Genome Res 2004; 14 (10A): 1902–1910.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73

    Jinek M, Doudna JA . A three-dimensional view of the molecular machinery of RNA interference. Nature 2009; 457 (7228): 405–412.

    CAS  Article  Google Scholar 

  74. 74

    Liang M, Liu Y, Mladinov D, Cowley AW, Trivedi H, Fang Y et al. MicroRNA: a new frontier in kidney and blood pressure research. Am J Physiol Renal Physiol 2009; 297 (3): F553–F558.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75

    Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (2): 281–297.

    CAS  Article  Google Scholar 

  76. 76

    Shukla GC, Singh J, Barik S . MicroRNAs: processing, maturation, target recognition and regulatory functions. Mol Cell Pharmacol 2011; 3 (3): 83–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Clifford RL, Singer CA, John AE . Epigenetics and miRNA emerge as key regulators of smooth muscle cell phenotype and function. Pulm Pharmacol Ther 2013; 26 (1): 75–85.

    CAS  Article  Google Scholar 

  78. 78

    Forman JJ, Legesse-Miller A, Coller HA . A search for conserved sequences in coding regions reveals that the let-7 microRNA targets Dicer within its coding sequence. Proc Natl Acad Sci USA 2008; 105 (39): 14879–14884.

    CAS  Article  Google Scholar 

  79. 79

    Esteller M . Non-coding RNAs in human disease. Nat Rev Genet 2011; 12 (12): 861–874.

    CAS  Article  Google Scholar 

  80. 80

    Mopidevi B, Ponnala M, Kumar A . Human angiotensinogen +11525 C/A polymorphism modulates its gene expression through microRNA binding. Physiol Genomics 2013; 45 (19): 901–906.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81

    Marques FZ, Campain AE, Tomaszewski M, Zukowska-Szczechowska E, Yang YH, Charchar FJ et al. Gene expression profiling reveals renin mRNA overexpression in human hypertensive kidneys and a role for microRNAs. Hypertension 2011; 58 (6): 1093–1098.

    CAS  Article  Google Scholar 

  82. 82

    Kemp JR, Unal H, Desnoyer R, Yue H, Bhatnagar A, Karnik SS . Angiotensin II-regulated microRNA 483-3p directly targets multiple components of the renin-angiotensin system. J Mol Cell Cardiol 2014; 75: 25–39.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83

    Wang K, Long B, Zhou J, Li PF . miR-9 and NFATc3 regulate myocardin in cardiac hypertrophy. J Biol Chem 2010; 285 (16): 11903–11912.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84

    Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell 2008; 15 (2): 272–284.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85

    Bátkai S, Thum T . MicroRNAs in hypertension: mechanisms and therapeutic targets. Curr Hypertens Rep 2012; 14 (1): 79–87.

    Article  CAS  Google Scholar 

  86. 86

    Kontaraki JE, Marketou ME, Zacharis EA, Parthenakis FI, Vardas PE . MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage. J Am Soc Hypertens 2014; 8 (6): 368–375.

    CAS  Article  Google Scholar 

  87. 87

    Santovito D, Mandolini C, Marcantonio P, De Nardis V, Bucci M, Paganelli C et al. Overexpression of microRNA-145 in atherosclerotic plaques from hypertensive patients. Expert Opin Ther Targets 2013; 17 (3): 217–223.

    CAS  Article  Google Scholar 

  88. 88

    Sayed AS, Xia K, Salma U, Yang T, Peng J . Diagnosis, prognosis and therapeutic role of circulating mirnas in cardiovascular diseases. Heart Lung Circ 2014; 23 (6): 503–510.

    Article  Google Scholar 

  89. 89

    Eskildsen TV, Jeppesen PL, Schneider M, Nossent AY, Sandberg MB, Hansen PB et al. Angiotensin II regulates microRNA-132/-212 in hypertensive rats and humans. Int J Mol Sci 2013; 14 (6): 11190–11207.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references


The study was supported by the Ministry of Science and Technology of China with ‘973’ grant 2012CB517804 and the National Natural Science Foundation of China with grants 81322002 and 81270333 to Dr Wang.

Author information



Corresponding author

Correspondence to Y Wang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Gong, L., Tan, Y. et al. Hypertensive epigenetics: from DNA methylation to microRNAs. J Hum Hypertens 29, 575–582 (2015). https://doi.org/10.1038/jhh.2014.132

Download citation

Further reading


Quick links