Genetic and Epigenetic Mechanisms Regulating Blood Pressure and Kidney Dysfunction

Abstract

The pioneering work of Dr Lewis K. Dahl established a relationship between kidney, salt, and high blood pressure (BP), which led to the major genetic-based experimental model of hypertension. BP, a heritable quantitative trait affected by numerous biological and environmental stimuli, is a major cause of morbidity and mortality worldwide and is considered to be a primary modifiable factor in renal, cardiovascular, and cerebrovascular diseases. Genome-wide association studies have identified monogenic and polygenic variants affecting BP in humans. Single nucleotide polymorphisms identified in genome-wide association studies have quantified the heritability of BP and the effect of genetics on hypertensive phenotype. Changes in the transcriptional program of genes may represent consequential determinants of BP, so understanding the mechanisms of the disease process has become a priority in the field. At the molecular level, the onset of hypertension is associated with reprogramming of gene expression influenced by epigenomics. This review highlights the specific genetic variants, mutations, and epigenetic factors associated with high BP and how these mechanisms affect the regulation of hypertension and kidney dysfunction.

High blood pressure (BP) is the most common health-related complication in the United States and worldwide populations, affecting an estimated 1.5 billion people globally.^1,2 High BP, also known as hypertension, is a primary modifiable risk factor of renal, cardiovascular, and cerebrovascular diseases, including stroke, coronary artery disease, myocardial infarction, atrial fibrillation, heart failure, and peripheral vascular disease.^1,3,4 For years, hypertension was defined as BP ≥140/90 mm Hg in adults; however, the latest report from the American Heart Association/American College of Cardiology recently updated this criterion to BP ≥130/80.⁵ The disability and death caused by high BP are manifested largely in the kidneys, heart, vasculature, and brain. These are collectively known as hypertensive end-organ disorders, and they account >10 million deaths globally each year.^2,6 The causes of hypertension have not been well defined, but certain conditions greatly increase the risk of disease, including aging, obesity, physical inactivity, diet, stress, chronic kidney disease, diabetes, and genetic family history.⁵ High BP and kidney diseases cost the US Health System an estimated $100 billion per year. High BP and renal disorders are regulated by complex, poorly understood genetic, and epigenetic mechanisms that exert significant influence via both heritable and environmental factors. The regulatory control mechanisms of high BP and kidney diseases, governed by intricate molecular and pathophysiological systems, indicate that genetic determinants and epigenetic factors govern gene regulation, expression, and function, which greatly influence preconditional settings and susceptibility to the development of hypertension and kidney injury and dysfunction.^7–10

BP is the result of cardiac output and vascular peripheral resistance, which are influenced by many physiological, neuroendocrine, and humoral functions. The pathogenesis of hypertension varies between individuals, although elevated vascular resistance is common to most cases^11,12; however, the molecular mechanisms of genetic and epigenetic regulation of BP are not well understood. Genes regulate heritable forms of essential hypertension and contribute to renal transport mechanisms,¹³ and the kidney plays a major role in the regulatory networks that predominately affect hypertension.^14,15 Over the past 30 to 40 years, genomic researchers have found associations between monogenic rare variants and single nucleotide polymorphisms (SNPs), mainly driven by causative mechanisms of RAAS (renin-angiotensin-aldosterone system), NPs (natriuretic peptides), the sympathetic neuronal system, endothelial dysfunction, and inflammation.^16–18 Alterations in the components of these pathways could lead to genetic and epigenetic perturbations that cause early stage hypertension. The current review highlights the salient features of the genomic and epigenomic aspects of high BP and renal dysfunction. Our understanding of the determinants, outcomes, and risk factors of hypertension has improved greatly in recent years. Enormous progress has been made in elucidating the genomic and epigenomic factors that control the etiology of high BP, including both monogenic and polygenic traits, integrating pleiotropic connectivity with other signals, and phenotypes consistent with lifestyle and environmental factors. This review is driven by the initial discovery and research works of Dahl, ^19–21 who established a relationship between high BP and genetics, salt (ie, environment), and the kidney.

GENETIC FACTORS AND THE REGULATION OF HIGH BP

Hypertension represents a complex heterogeneous condition governed by multiple quantitative genes. The elements regulating high BP are known to have a strong genetic component, but the specific candidate genes involved in disease pathogenesis are poorly defined.^8,17,22 Current drug therapy for high BP, including ACE (angiotensin-converting enzyme) inhibitors, ARBs (angiotensin receptor blockers), calcium antagonists, and blockade of the adrenergic system, are marginally effective but do not fully prevent the occurrence of high BP.²³ Therapeutic treatment strategies using genetic approaches and personalized medicine have been given high priority. Among the large number of genetic variants identified by genome-wide association studies (GWASs), many produce quantitative-aggregate effects, indicating a risk of polygenic hypertension.^24–26 High BP has considerable heritability,^13,27,28 and genetic and epigenetic elements represent promising candidates for diagnosis and control of high BP in humans. Inflammation, an integral component of immune responses, appears to be a critical regulator of BP. This relationship offers new perspectives and translational approaches to the pathology of hypertension.^29,30 SH2B3/LNK (lymphocyte adaptor protein) negatively regulates downstream signaling of proinflammatory cytokines.³¹ GWASs have discovered a strong association between polymorphism of Sh2b3 (SH2B adaptor protein 3) and human hypertension.^32,33 The loss of Sh2b3 in mice increases BP and kidney disorders with inflammatory responses.³³ Interestingly, an SNP in Sh2b3/Lnk (rs3184504) in rodents promotes hypertension and kidney disorders via increased levels of T-cell IFN-γ (interferon gamma).¹⁸

Genetic Variants and Polymorphisms Regulating High BP

Genetic factors play a vital role in affecting BP in humans and experimental animal models. Because the association of BP with renal, cardiovascular, and neuronal risk is dynamic and continuous, small increases in systolic and diastolic BP can confer severely harmful effects.^34,35 The determining factors underlying the interindividual differences and variability in BP are poorly understood. The RAAS, adrenergic system, and endothelin pathway are all known to mediate increases in BP; however, investigations of these pathways have not produced strong evidence of genetic involvement in variations of BP.^36–38 Genetic studies of the NPs system have revealed some critical and intriguing clues on the role of genes in regulating BP homeostasis (Table). The NP hormones, including ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), are released from the heart, activate GC-A (guanylyl cyclase)/NPRA (natriuretic peptide receptor A), and effectively lower BP.^50–53 The common genetic variants at the precursor locus of Nppa (ANP precursor) and Nppb (BNP precursor) have been associated with increased circulating concentrations of ANP-BNP with BP-lowering properties.³⁸ SNPs characterized at Nppa and Nppb loci in 14 743 individuals of European ancestry showed that rs5068 and rs19835 were associated with reduced systolic and diastolic BP, which correlated with high concentrations of NPs and reduced risk of hypertension. These SNPs were also found to contribute to interindividual variations in BP regulation.³⁸ The clinical etiology of BP and NP biomarkers could establish negative-positive feedback mechanisms that maintain a balance between the negative effect of NPs on BP, but BP exerts a positive effect on the release of NPs in the circulation. Meta-analyses of BP in humans have shown that variants of Nppa, Nppb, and Npr1 (encoding NPRA) are strongly associated with BP.^40,49 Among the polymorphisms and mutations of genes associated with BP in humans, the NPs system has been most extensively studied (Table).

Table.

Selected Gene Mutations and Polymorphisms of Nppa, Nppb, and Npr1 Associated With Hypertension

BP is a polygenetic multifactorial disorder affected by genetic variations; however, the identification of candidate genes remains incomplete and requires more thorough investigation. Since high BP is a heterogeneous disease syndrome, the identification of specific gene variant(s) may facilitate progress toward personalized treatments. A precision medicine approach could prove to be a major treatment strategy for hypertension and associated complications such as acute kidney injury, neurological disorders, and cardiovascular dysfunction. All BP subsets require vigilant attention and care and are of high clinical importance. Epidemiological evidence and family studies have shown a considerable heritable component for clinical systolic (≈40%) and diastolic BP (≈30%), which are associated with hypertension.^38,54–56 The BP phenotype of monozygotic twins is more highly correlated than that of dizygotic twins or parental/grandparental history of hypertension.^57–59 Genomic studies have indicated a strong polygenic trait in the architecture of BP.^25,60 GWASs using improved genotyping and sequencing methods have shown that the genetic component of hypertension comprises over 30 major monogenic rare variants and almost 1500 ultra-rare SNPs.^6,17 Although the immediate application of GWASs results is not yet feasible in translational studies or clinical settings, they offer opportunities for risk prediction in personalized medicine.^61–63 GWASs have identified a host of SNPs with mild effects on BP that may provide critical insights into pathology of disease. Targeting SNPs based on genetic ancestry may lead to new approaches to precision medicine to treat patients with high BP and kidney dysfunction. Most existing genetic studies on SNPs have reported pooled data from both male and female subjects of varying ages; future studies should treat sex as a biological variable for a more complete understanding of these mechanisms.

Regulatory Elements and Transcription Factors in Modulation of BP

The expression and regulation of candidate genes are usually governed by multiple response elements and TFs (transcription factors) in their promoter regions.^64,65 These response elements and TF sites may interact physically with regulatory domains ≈50–60 kb upstream of the active sites of promoters.^66,67 Genetic dissection of super enhancers has demonstrated that these elements selectively regulate gene expression under both basal and disease conditions.^68–70 The effect of ANG II (angiotensin II) on BP seems to be mediated by several TFs in different organ systems.^71,72 Among the RAAS components, AGT (angiotensinogen) is regulated by the TF, FOXO 1 (fork-head box class 1), and its loss in mice, reduced plasma AGT and ANG II that significantly lowered BP.⁷³ Likewise, several TFs, including CREBP (cAMP-response element binding protein), GATA-1 (GATA-binding factor 1 also termed erythroid transcription factor), and NF-κB (nuclear factor-light-chain-enhancer of activated B cell), may interact with AGT promoters to affect human hypertension. A functional deletion mutation in 5′-flanking region of Npr1 in Japanese individuals exhibited reduced receptor activity associated with essential hypertension.⁴⁵ The transcriptional activity of deleted allele was 30% lower than in subjects with wild-type alleles.

A family of TFs, including Ets (E26-avian leukemia oncogene 1, 5′ domain), interacts with GGAA/T (a repeat region as a sequence motif) cis-acting element and enhances angiogenesis and inflammatory responses in hypertension.^74,75 Ets-1 enhances vascular and renal fibrogenic responses and ultimately causes high BP and vascular disorders.^74,76 Ets-1 seems to act as a double-edged sword. On the one hand, it enhances the action of ANG II, which triggers high BP; on the other hand, it also increases the expression and activation of Npr1, which directly lowers BP.^77,78 Our previous studies demonstrated that all-trans retinoic acid signaling recruited Ets-1 and Sp1 (stimulatory protein), which potentially enhanced the functional expression of NPRA, which plays a critical role in the pathophysiology of high BP (Figure 1).

Figure 1.

A model depicts the interactive mechanisms between regulatory elements and transcription factors that govern lowering blood pressure and renal dysfunction: In its inactive mode, the corepressor is bound to all-trans retinoic acid (ATRA) receptors (RAR and RXR), which prevents the binding of Ets (E26-avian leukemia oncogene 1, 5′ domain) with Npr1 promoter. Upon stimulation with ATRA, the corepressor dissociates from the RAR and RXR and Ets-1/Sp1 (stimulatory protein) is recruited to activate an RAX/RXR/Ets-1 complex that binds to Npr1 promoter and activates transcription. Increased Npr1 expression activates ANP (atrial natriuretic peptides)-BNP (B-type natriuretic peptide)/NPRA (natriuretic peptide receptor A) signaling, which reduces BP and kidney dysfunction. NaBu indicate sodium butyric acid; PCAF, p300/cAMP-response element binding factor; RAR, retinoic acid receptor; and RXR, retinoic acid x receptor. Data derived with modification from Kumar et al.⁷⁷

One study showed that the common nucleotide variant in Mmp7 (encoding matrix metalloprotein 7) promoter increased the risk of hypertension in a South Indian population by enhanced interaction with the TF, CREB (cAMP-response element binding) protein.⁷⁹ The Mmp7 promoter polymorphism, A-181G enhanced MMP7 protein levels via increased interactions with CREB, triggering the risk of hypertension. Several kinases activated by ANG II have been found to stimulate the phosphorylation of CREB, which has a role in vascular remodeling associated with hypertension.⁷⁹ Our own studies indicate that CREB facilitates the ANG II-mediated repression of Npr1 transcription and its function in mouse aortic rings ex vivo.⁸⁰ The inhibitory effect of ANG II on NPRA/cGMP signaling is transduced by direct repressive effect of CREB on Npr1 transcription. Another TF, HSF-4a (heat-shock factor-4a), also represses the transcription and expression of Npr1 in mouse mesangial cells and vascular smooth muscle cells, thus, blocking the signaling of ANP/NPRA.⁸⁰ ANG II increases the HSF-4a and heat-shock protein 90 complex, which negatively regulates NP receptors.⁸¹ Those findings suggest that the hormonal signal of ANG II is required for the activation of CREB and HSF-4a to exert a repressive effect on Npr1 transcription (Figure 2). We further showed that the E2 box repressor δEF1 (delta-crystallin factor enhancer-binding factor 1) is regulated by TGF-β1 (transforming growth factor-beta 1), which acted negatively on Npr1 transcription, blocking ANP/NPRA signaling.⁸² Further studies are needed to clarify the role of TFs in human hypertension. Most studies have included only males, leaving a research gap in our understanding of sex dimorphism.

Figure 2.

The role of ANG II (angiotensin II)-mediated transcription factors HSF-4a (hear-shock factor-4a) and CREB (cAMP-response element-binding protein) in the repression of Npr1 gene transcription that increases vascular resistance and blood pressure (BP): ANG II represses Npr1 transcription and expression via AT1R (angiotensin receptor type 1), which enhances phosphatidyl inositol 3-kinase (PI-3K) and tyrosine kinase (TK) signaling. HSF-4a and CREB are thus recruited to the Npr1 promoter, which decreases the transcription and expression of Npr1. The inhibition of Npr1 decreases renal and vascular responsiveness, increasing BP. HATs indicates histone acetylases; and HDAC, histone deacetylase. Data derived with modification from Arise et al.⁸⁰

EPIGENETIC LANDSCAPE AND REGULATION OF BP

Epigenomics holds great promise for delineating the underlying mechanisms of high BP and kidney diseases. Besides genetic elements, BP is affected by alterations in biological pathways, which are directly influenced by environmental factors. Epigenetic mediators act at the genome- or near-genome level and form a bridge between gene and environment. Epigenetics is defined as heritable alterations in gene expression patterns that are not caused by a change in the nucleotide base sequence of DNA and can be reversible with changing environmental factors.^83,84 Major epigenetic modifications include DNA methylation, histone modifications, and RNA-based mechanisms.^11,85,86 Epigenome-wide investigations of high BP have suggested that epigenetic changes associated with DNA methylation and histone modifications activate gene expression regulation, and function, initiating the onset and progression of hypertension, kidney injury, and cardiovascular dysfunction.^10,87,88 Experimental approaches targeting key epigenetic enzymes, namely DNMTs (DNA methyl transferases), HATs (histone acetylases), HDACs (histone deacetylases), and HMTs (histone methyl transferases), could provide new tools for the diagnosis, treatment, and prevention of hypertension. The kidney is a rich source of acetylated lysine, a critical element of epigenetic programming, including BP.⁸⁹

The genetic sequence is usually identical in every cell of an individual organism and remains constant though the lifespan, while epigenomic mediators may vary between cell types. They are influenced by changes in environmental conditions including pathology, age, hormones, sex, diet, and drugs.^11,85 The key epigenetic regulators of gene expression may influence numerous mechanisms regulating BP and kidney dysfunction. Because epigenetic modifications are reversible, these changes may reveal new therapy targets for hypertension and kidney diseases. Epigenetics of DNA methylation, histone modifications, and RNA therapeutics, may reveal promising new treatment strategies for human hypertension and kidney dysfunction.^90,91

DNA Methylation

DNA methylation occurs predominantly on cytosine-phosphate-guanine (CpG) dinucleotides and is a universal epigenetic modification of gene expression in mammalian cells.^92,93 The methylation of DNA attenuates gene expression to offset chromosomal instability and may influence hypertension and chronic kidney disease.^94–96 This is a critical process that may transfer genetic information to offspring via the regulation of DNMTs, which are classified into 3 subclasses: writing enzymes, erasing enzymes, and reading enzymes.⁹⁷ The writing enzymes (DNMT1, DNMT2a, and DNMT3b) catalyze the addition of methyl groups to DNA. Among them, DNMT1 mimics the initial methylation pattern before DNA replication. DNMT3a and DNMT3b regulate de novo DNA methylation and could establish a new methylation pattern for unmodified DNA. The reading enzymes recognize methyl groups and predominantly affect gene expression, while eraser enzymes usually modify and remove methyl groups.^98,99 Changes in DNA methylation may have critical and significant roles in hypertension, chronic kidney disease, and inflammation.^96,100–102

Genetic variants identified in the regulation of BP indicate a role for DNA methylation.¹⁰³ The methylation of Ece gene (encoding endothelin converting enzyme) seems to be associated with the pathological mechanisms of hypertension.¹⁰⁴ Maternal lifestyle and diet have been linked with perinatal differentially dmCpGs (DNA methylated CpG dinucleotide) signature, associated with childhood arterial stiffness and development of hypertension.¹⁰⁵ The methylation of corin promoter has been reported to be associated with complications of stroke in patients with hypertension.¹⁰⁶ DNA methylation occurring in renal medulla plays a key role in the onset and development of salt-induced hypertension.¹⁰⁷ Interestingly, the inhibition of DNMTs suppressed salt-induced hypertension, which was associated with decreased infiltration of immune cells in the kidneys.¹⁰⁸ DNA methylation of At1b gene (encoding angiotensin type 1b receptor) plays a role in high-salt-diet-induced hypertension.⁸⁸ DNA methylation patterns can be altered under stress and disease conditions.¹⁰⁹ DNMTs add a methyl group to the carbon atom at position 5 of cytosine, adjacent to guanine, to yield 5-methylcytosine (5MC), which is associated with gene repression.^110,111 Other types of DNA modifications include 5 HMC (hydroxymethylation) and formyl cytosine (5 FC) as means of reversing gene expression.¹¹² TET (ten-eleven translocation) enzymes oxidize 5 MCs to 5 HMCs and catalyze the conversion to 5 FC, which is used in DNA base excision-repair process.¹¹³ TET enzymes are considered a significant target of future therapies for hypertension and kidney diseases by reversing the nature of gene repression.

DNA methylation may allow the identification of potential risk factors from patient to patient to determine whether differences exist in DNA methylation patterns in the blood cells of hypertensive individuals. The total 5 MC level was found to be lower in the peripheral blood of patients with essential hypertension and those with stage-1 hypertension.¹¹⁴ Genome-wide lineage and GWASs have shown SNP variants to be linked with differential DNA methylation patterns in hypertension.¹⁰³ Hypermethylation of DNA in the α-subunit of the ENaC (epithelial Na⁺ channel) gene (Scnn1a) at CpG islands increased the risk of hypertension.¹¹⁵ CpG hypermethylation of the amiloride-sensitive sodium channel beta-subunit (Scnn1b) gene is also associated with hypertension, and antihypertensive therapy affected CpG levels in human patients.¹¹⁶ Thus, hypermethylation of CpG islands in the exons may be associated with hypertension. The majority of studies on the role of DNA methylation in BP have either been performed on males only or offer combined analysis of both men and women. There is an urgent need to explore and reveal gender and age differences in future studies.

Histone Modifications

Histones are basic proteins whose modifications predominantly occur in the amino terminal of basic residues lysine and arginine, which play critical roles in chromatin remodeling and gene expression.^117,118 Epigenetic mediators govern pathophysiological mechanisms via their influence on gene expression using histone modifications, including acetylation, deacetylation, and methylation. Acetylation and deacetylation are catalyzed by HATs and HDACs, respectively, and their expression seems to be associated with hypertension and renal dysfunction.^89,119 A dynamic reversible equilibrium is maintained between HATs and HDACs to relax or condense chromatin thus enhancing or repressing, respectively, gene transcription and expression in disease states (Figure 3).

Figure 3.

The interactions between histone acetylases (HATs) and histone deacetylase (HDACs), which influence active and repressive modes of gene transcription and expression: external or internal stimuli activate HATs, which catalyze histone acetylation. As a result, the chromatin becomes open and DNA is accessible to bind with TFs (transcription factors), which activates gene transcription, expression, and function. On the contrary, upon the activation of HDACs, the acetyl group is removed from histone and as a result, histone is closed and DNA becomes inaccessible to bind with TFs, repressing gene transcription and inhibiting gene function. After deacetylation, histone may be heavily methylated, which further inhibits gene expression.

HATs catalyze the transfer of acetyl group to lysine residues at the N terminus of histones allowing the negatively charged acetyl group and positively charged lysine group to bind each other, which promotes DNA-histone relaxation to induce gene transcription and expression.¹²⁰ Acetylation enhances gene transcription through its reversible action in histones and interacting proteins and is considered an active histone mark. The interaction of HAT p300 and cAMP response element-binding protein (CBP) forms the CBP/300 complex, which enhances gene transcription.¹²¹ CBP/p300 complex also recruits other HATs, including PCAF (p300/CBP-related factor), which robustly catalyzes the acetylation process during gene transcription.^122,123 Acetylation of lysine initiates functional changes via its affinity to binding proteins, which regulates gene expression. The acetyl groups of acetylated histones are removed by HDACs in a coordinated manner, forcing the chromatin to condense and suppress gene transcription.¹²⁴ Our studies have shown that the deacetylate and methylated histone marks were responsible for high BP and kidney disorders, on the contrary the enhanced histone acetylation reduced BP and renal dysfunction in haplotype Npr1 KO (gene-knockout) mice.^77,125

Based on their structural similarities and substrate specificities, HDAC family members can be divided into 4 groups: class I consists of HDAC 1, 2, 3, and 8; class II is divided into 2 subclasses, class IIa (HDAC 4, 5, 7, and 9), and class IIb (HDAC 6 and HDAC 10); class III shows specificity to nicotinamide adenine dinucleotide (NAD⁺), including SIRT (sirtuins) 1 to 7; and class IV comprises one member, HDAC 11. Kidney is rich in the acetylated lysine proteins and expresses several HATs and HDACs.^126,127 In mouse and rat kidney, all 11 HDACs are expressed in nephron segments; however, human kidney also expresses all HDACs, except HDAC 7.^128–130 HDACi (HDAC inhibitors) are among the popular epigenetic drugs currently being evaluated for many diseases, including cancer, cardiovascular disease, hypertension, and neurological disorders. Gene-disrupted Npr1 KO haplotype mice, exhibiting high BP and renal dysfunction, showed significantly elevated renal HDAC 1 and HDAC 2 proteins.¹²⁵ Treatment of mutant Npr1 haplotype mice with the HDACi sodium butyrate-enhanced HAT activity and acetylated levels of renal active histone marks H3K9me2 (histone 3 lysine 9 dimethylation), H3K9me3 (histone 3 lysine 9 trimethylation), and H3K27me3 (histone 3 lysine 27 trimethylation) and reduced BP in these animals.^77,125,131 Treatment with HDACi, trichostatin A attenuated repressive histone marks and also reduced BP (Figure 4). We demonstrated that ANG II enhanced the activity of class I HDAC 1 and HDAC 2, reduced histone acetylation, and inhibited the transcription of Npr1, thereby diminishing vascular reactivity ex vivo.⁸⁰ We suggested that ANG II-mediated inhibition of Npr1 transcription and receptor function may provide new molecular targets for the treatment and prevention of hypertension. The pan-HDAC inhibition with trichostatin blocked aldosterone-mediated ENaC activity and Na⁺-retaining effect of aldosterone.¹³² Further studies also suggested that HDACi prevented the salt-sensitive hypertension.¹³³ The adverse effects of HDACi seem to include diarrhea, vomiting, and altered BP in humans.^134,135 Indeed, a large gap exists that requires research on the specificity of HDACi in patients with high BP and kidney disease. Considering biological variables such as sex and age, also remain to be extensively studied to develop therapeutic regiments for prevention and treatment of hypertension and renal disorders.

Figure 4.

A graphic model illustrates the role of histone deacetylase inhibitors and histone acetylase activators mediating the transcription of Npr1 regulating blood pressure and kidney disorders: in the inactive mode of gene repression, histone deacetylases (HDACs) are bound with the corepressor and associated with chromatin. Upon exposure to HDACi (HDAC inhibitor), HDAC and corepressor are inhibited and dissociated from the chromatin. As a result, histone acetylases (HATs) are activated, which acetylate histones, allowing coactivators and transcription factors to be recruited to DNA of target genes and activate transcription that reduces high BP and renal dysfunction. HATs indicates histone acetylases; HDAC, histone deacetylase; TSA, trichostatin A; MGCD, mocetinostat; PCAF, p300/cAMP response element binding factor; TFs, transcription factors; H3K9me2/3, histone 3 lysine di/tri methylation; and H3K9ac, histone 3 lysine 9 acetylation. Data derived with modification from Kumar et al.¹³¹

Histone methylation is catalyzed by HMT, which transfers methyl groups to lysine and arginine using S-adenosine methionine. Methylation of histone is associated with both positive and negative target gene transcription.^136,137 Lysine methylation of H3 at fourth site is associated with transcriptional activation; however, lysine methylation at ninth and 27th sites are involved in gene silencing.^118,138 The positive histone methylation includes H3K4me2/3, H3K36me2/3, and H3K79me2, which activate gene transcription. The negative histone methylation marks include H3K9me2/3, H3K27me3, and H4K20me3, which inhibit gene transcription. The methylation of histone (H3K9me2 and H3K9me3) governs heterochromatin formation and also inhibition of gene transcription.^139,140 Histone methylation is a dynamic process usually associated with gene silencing and negative expression.¹⁴¹ Our studies demonstrated that Npr1 KO haplotype mice exhibit high BP, renal injury, and enhanced levels of repressive histone marks (H3K9me2, H3K9me3, and H3K27me3) in the kidneys.⁷⁷ Studies examining gender-, sex-, and age-related effects on histone modification of hypertension and kidney disorder remain scarce. More rigorous investigations are urgently needed to develop novel, targeted therapeutic strategies and treatment approaches for men and women of all ages.

Noncoding RNAs

LncRNAs (long-noncoding RNAs) contribute to the programming of hypertension. Systemic expression of miRs (microRNA) has a significant impact in patients with hypertension.^142,143 miRs are a subclass of naturally occurring LncRNA that control gene expression in cardiovascular diseases, including hypertension. The regulatory role of miRs concerns the inhibition of gene expression and degradation of messenger RNAs. An anomalous expression profile of miR seems to be associated with pathological conditions like hypertension, kidney injury, and cardiovascular dysfunction. Major miRs present at elevated systemic levels in patients with high BP include miR-11, miR-22, miR-92a, miR-222, mir-506-3p, miR-516b, miR-600, and miR-606,^143,144 among others. Several miRs have also been found to be decreased in patients with hypertension, including miR-133, miR-143; miR-186, miR-296-5p, miR-296, and miR-518.¹⁴⁵

Many miRs are known to interact with the components of RAAS, including miR-34b, mir-181a, miR-361-5p, and miR-362-5p, which influence target gene expression.^146–148 The expression of miR-21 has been linked with increased BP, likely targeting decreased expression of eNOS (endothelial NO synthase) in hypertensive individuals.¹⁴⁹ In trophoblasts, miR-181-5p and miR-663 inhibited renin expression, and reduced ANG II levels, lowering BP.¹⁵⁰ The miR-483-3p was found to inhibit the expression of AGT and ACE 1 and lower BP.¹⁵¹ The overexpression of miR-155-5p was reported to decrease ACE 1 and ANG II formation, thus reduced BP and vascular remodeling in spontaneously hypertensive rats.¹⁵² MiR-505 has been suggested as a marker of hypertension-induced endothelial dysfunction in spontaneously hypertensive rats.¹⁵³ Human patients with hypertension subjected to postexercise oxygen intake showed increased expression of miR-200-5p with decreased BP.¹⁵⁴

Genetic data suggest that polymorphisms in certain LncRNAs, including rs133049, rs10757274, rs2383207, and rs10757278, were found to increase the risk of hypertension.¹⁵⁵ Similarly, the expression of the LncRNA NR-104 181 is associated with a high burden of hypertension in human patients.¹⁵⁶ Older patients with hypertension show lower plasma levels of miR-181-5p, which correlates with a simultaneous increase in plasma ANG II.¹⁵⁷

Alterations of Epigenetic Mechanisms in Hypertension

The epigenetic regulations of BP are not fully understood; however, the role of epigenetics in hypertension holds valuable potential for the identification of new biomarkers for therapeutic targets. New drugs based on the epigenomic potential to treat high BP and renal dysfunction offer new strategies to protect human lives against malignant hypertension. It is well recognized that BP is influenced by genetic and environmental factors, but the mechanisms underlying epigenetic alterations are less understood. Epigenetic programming caused by adverse fetal environments in utero, or environmental and social stressors early in the lifespan, may contribute to the eventual onset of hypertension in adulthood.^158,159 Epigenomic changes induced by environmental factors can be transmitted to subsequent generations and lead to hypertension.¹⁶⁰ Although epigenomic alterations participate in the mechanisms of BP elevation, these changes could also be a consequence of altered BP. Further investigations are urgently needed to clarify the causal agents of epigenomic changes and their roles in the development of hypertension in humans. Few studies have reported gender-, sex-, or age-related differences in the epigenetic mechanisms regulating BP and kidney disorders. This information is critical to establishing targeted therapies and must be explored in future investigations.

CONCLUSIONS

The genetic architecture has profound influence on the mechanisms affecting high BP. A wide spectrum of genetic variants, from high-impact ultra-rare variants to common SNPs, have opened new avenues for researchers using pharmacogenomics to acquire a more thorough understanding of BP and how it is controlled. Genomic and epigenomic advances have bridged gaps in knowledge, allowing us to better understand the essential roles of genetic variants, epigenomics, and gene-environment interactions to facilitate the practice of clinical personalized genomics. The dynamic nature of epigenetics could provide a more accurate knowledge of the factors associated with environment-gene interactions. The application of pharmacogenomics is critical for documentation of interindividual variation in BP that may lay the groundwork for personalized treatment therapy. The knowledge of epigenetic alterations in patients with hypertension may reveal insights into the pathophysiologic processes of high BP and renal disorders and lead to new targets for the novel therapeutic treatment approaches. Future investigations of genetic and epigenetic resources may provide a foundation for personalized treatments and offer new directions for prevention and intervention of hypertension and kidney diseases. Future studies must integrate GWASs and transcriptomic results with epigenomic data to test their validity using both reverse and forward investigations, in both experimental animal models and humans in translating basic research into clinically effective strategies in patients. This review sought to highlight recent advances in our knowledge of the genomic and epigenomic factors associated with the onset and development of high BP and renal disease, particularly genetic variants, DNA methylation, histone modifications, and LncRNA regulation. An improved understanding of the genomic and epigenomic regulation of high BP and renal dysfunction will lead to the identification of novel molecular targets that may in turn pave the way for new drugs and treatment strategies for hypertension.

ARTICLE INFORMATION

Acknowledgments

The author thanks Mrs Kamala Pandey for article preparation and Ms. Loula Burton for reading the article. Also, the author sincerely thanks current and previous members of the laboratory research team for their excellent contributions.

Sources of Funding

This work was supported by the research grants from the National Institutes of Health (HL062147 and DK133833).

Disclosures

None.