Pathogenesis Of Essential Hypertension Research Articles

Treatment of spontaneously hypertensive rats during pregnancy and lactation with the antioxidant tempol lowers blood pressure and reduces oxidative stress.

Genetic and environmental factors interact in a complex manner in the pathogenesis of essential hypertension in humans. Oxidative stress is considered one of the more important environmental factors. We used the spontaneously hypertensive rat (SHR) model to test whether continuous feeding with the antioxidant tempol reduces maternal oxidative stress during pregnancy and potentially contributes to the prevention of cardiovascular disease onset. Pregnant female rats were divided into control and tempol-treated groups. Tempol was continuously administered in drinking water. The administration period lasted approximately 40 days, from the confirmation of a vaginal plug until birth of the pups and their subsequent weaning. The blood pressure (BP) of each adult female was measured three times during pregnancy and post parturition. Milk was collected three times from nursing mother rats in the immediate postpartum period. Markers of oxidative stress were measured: 8-hydroxyl-2'-deoxyguanosine (8-OHdG) levels in milk during the experimental period and 8-OHdG and corticosterone levels in urine of adult and neonatal rats. The urinary level of 8-OHdG in the tempol-treated group was significantly lower than that in the control group. Corticosterone levels were significantly lower in urine of neonatal rats from the tempol-treated group compared with the levels of the control group. The levels of total antioxidant in milk were significantly greater in the tempol-treated group than in the control group. This study demonstrated that continuous administration of tempol to pregnant SHRs reduced maternal oxidative stress and contributed to reduced oxidative stress in neonatal rats.

Monte Carlo Optimization Based QSAR Modeling of Angiotensin II Receptor Antagonists

The pathogenesis of essential hypertension, congestive heart failure, and reno-vascular hypertension is related to angiotensin II. This study presents QSAR modeling for a set of compounds acting as angiotensin II receptor antagonists based on the Monte Carlo optimization with molecular graph-based and SMILES notation based descriptors. Conformation independent QSAR models were developed for three random splits. Various statistical approaches were used to assess the statistical quality of the developed models, and the obtained results were very good. This study used a novel statistical metric known as the index of ideality of correlation for the final assessment of the model, and the results that were obtained suggested that the model was good. Also, molecular fragments which account for the increases and/or decreases of a studied activity were defined and then used for the computer-aided design of new compounds as potential angiotensin II receptor antagonists. The final assessment of the designed inhibitors, was performed with the use of molecular docking studies, highlighting exceptional correlation with the QSAR modeling results. The methodology which is presented in this research can be applied for seeking new agents for cardiovascular disorders treatment by angiotensin II receptor antagonism.

INCREASED IONIZED CALCIUM-MAGNESIUM RATIO IN ELDERLY HYPERTENSIVES

Objective: Alterations in the metabolism of calcium and the biofactor magnesium can be involved in the pathogenesis of essential hypertension. Serum magnesium concentrations only insufficiently reflect disorders in magnesium handling in humans, as only about 1% of total body magnesium stores are in blood. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium and magnesium (TRPM 6 and 7) channels and a sodium magnesium antiport. An increased calcium-magnesium ratio is known to be involved in the development of atherosclerosis. Early onset of this disorders are known in hypertension. Design and method: We present a study in 18 hypertensive elderly concerning ionized magnesium concentrations and ionized calcium-magnesium ratio in blood measured by a Prime Plus apparatus by NOVA Medical, Andover, USA. Results: In 18 elderly hypertensives (9 male/9 female with normal renal function) ionized magnesium was measured 0.55 +/- 0.04 mmol/l (normal range: 0.54 - 0.80 mmol/l). The ionized calcium-magnesium ratio was 2.33 +/- 0.18 (normal range below 2.40)(p< 0.05). Data are means +/- SD. ANOVA was used for statistical evaluation. About 40% of elderly hypertensives showed an significantly increased ratio of ionized calcium and magnesium, which is well known to be a marker for the development of arteriosclerosis. Conclusions: As described earlier, a deficiency in the biofactor magnesium can be involved in the pathogenesis of essential hypertension. Ionized magnesium data, as presented here, are rare, but ionized magnesium is the active magnesium in the body regulating about 600 enzymatic reactions. The significantly increased ratio of ionized calcium and magnesium is important in the development of arteriosclerosis often resulting in stroke or heart insufficiency in hypertension.

G Protein-Coupled Receptor 37L1 Modulates Epigenetic Changes in Human Renal Proximal Tubule Cells.

Renal luminal sodium transport is essential for physiological blood pressure control, and abnormalities in this process are strongly implicated in the pathogenesis of essential hypertension. Renal G protein-coupled receptors (GPCRs) are critical for the regulation of the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Recently, we showed that GPCR 37L1 (GPR37L1) is expressed on the apical membrane of renal proximal tubules (RPT) and regulates luminal sodium transport and blood pressure by modulating the function of the sodium proton exchanger 3 (NHE3). However, little is known about GPR37L1 intracellular signaling. Here, we show that GPR37L1 is localized to the nuclear membrane, in addition to the plasma membrane in human RPT cells. Furthermore, GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and enhance NHE3 transcription. Overall, we demonstrate the direct role of a nuclear membrane GPCR in the regulation of renal sodium through epigenetic gene regulation.

Estimation of Serum Calcium Level in the Patients of Hypertension

Background: Hypertension is one of the leading progressive cause of mortality and morbidity in developed as well as developing countries all over the world. Intracellular and extracellular ions of the body regulate the hemostasis of blood pressure. Objective: To estimate the serum calcium level in the patients of newly diagnosed cases of hypertension with normotensive set of subjects. Methodology: This case comparative study was conducted at the medical OPD of Bilawal Medical College and LUMHS Hospital Hyderabad and Jamshoro. 100 subjects were chosen and divided into two groups: 50 normotensive as a control group and 50 hypertensive as a case study group. Selection of samples was done on the basis of the non-probability technique. A sphygmomanometer was used to measure blood pressure, and a kit method was used to measure serum calcium levels. The statistical analysis of the data was carried out by SPSS version 22 by applying the student t test. Results: The mean age of control group subjects was 44 ± 6 years and control group was 42 ± 7 years. The mean systolic Blood pressure of control group was 110 ± 5 mmHg, while in case study group it was 140 ± 10 mmHg. The mean Diastolic blood pressure of control group was 80 ± 5 mmHg, while in case study group it was 105 ± 5 mmHg. The mean serum calcium level in control group was 9.82 ± 0.68 mg/dl and in case study group it was 8.45 ± 0.47 mg/dl. There was significant (p <0.05) difference of serum calcium level was observed in case study group (hypertensive subjects group). Conclusion: This study concluded that disturbance in intracellular calcium levels can be one of contributory factor in the pathogenesis of essential hypertension. Keywords: Essential Hypertension, Serum Calcium, Intracellular Calcium, Blood Pressure.

Essential Hypertension Pathogenesis: Merely a Sympathetic Hyperactivity? A series of 10 Patients

Essential Hypertension Pathogenesis: Merely a Sympathetic Hyperactivity? A series of 10 Patients

Chromodomain Helicase DNA Binding Protein 1-like, a negative regulator of Forkhead box O3a, promotes the proliferation and migration of Angiotensin II-induced vascular smooth muscle cells

ABSTRACT Essential hypertension (EH) represents a major risk factor for stroke, myocardial infarction, and heart failure. Dysregulated proliferation and migration of vascular smooth muscle cells (VSMCs) play an important role in pathogenesis of EH. This study aims to investigate the effect of Chromodomain Helicase DNA Binding Protein 1-Like (CHD1L) on Angiotensin II (AngII)-induced VSMCs injury and reveal the underlying mechanism. The expression of CHD1L in EH patients was determined by bioinformatics analysis, and then it was silenced in AngII-induced VSMCs to detect the changes in cellular functions including proliferation, migration, invasion and phenotypic switching via CCK-8, EDU staining, wound healing, transwell and Western blot assays, respectively. Inflammation and oxidative stress were also measured by detecting related markers via commercial kits. After confirming the binding sites between forkhead box O3A (FOXO3a) and CHD1L and their negative association by bioinformatics analysis, FOXO3a was further silenced, and the cellular functions were assessed again to reveal the underlying mechanism. Results showed that CHD1L was highly expressed in EH, and interference of CHD1L suppressed the proliferation, migration, invasion and phenotypic switching in VSMCs. Inflammation and oxidative stress were also restrained by CHD1L knockdown. After validating the negative role of FOXO3a in regulating CHD1L, it was found that FOXO3a abrogated the effect of CHD1L knockdown on the cellular functions of AngII-induced VSMCs. In conclusion, FOXO3a suppresses the proliferation and migration of AngII-induced VSMCs by down-regulating CHD1L.

Eukaryotic elongation factor 2 kinase inhibitor, A484954 induces diuretic effect via renal vasorelaxation in spontaneously hypertensive rats

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K), alternatively known as calmodulin-dependent protein kinase III, inhibits protein translation via phosphorylating its sole substrate, eEF2. We previously demonstrated that expression and activity of eEF2K change in mesenteric artery from spontaneously hypertensive rats (SHR) with aging and that eEF2K is involved in pathogenesis of essential hypertension. In addition, we have recently revealed that acute intravenous injection with A484954, a selective eEF2K inhibitor, lowers blood pressure specifically in SHR partly via inducing vasorelaxation. In this study, we examined whether A484954 induces diuretic effect. After male SHR and normotensive Wistar Kyoto rats (WKY) were given a single intraperitoneal injection of A484954 (2.5 mg/kg, 0.5–9 h), urine was collected using metabolic cage. Contraction of isolated renal arteries form SHR was isometrically measured. While A484954 did not induce diuretic effect in WKY, it increased urine output, water intake, and urinary sodium excretion in SHR. A484954 (10 μM) induced vasorelaxation in isolated renal arteries, which was inhibited by a β-adrenergic receptor antagonist, propranolol. It was confirmed that A484954 increased renal blood flow in SHR as measured by renal ultrasonography. In summary, it was for the first time revealed that A484954 induces diuretic effect in SHR at least partly via renal vasorelaxation through β-adrenergic receptor.

Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension.

Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

Effect of lisinopril therapy on serum leptin, oxidative stress and C-reactive protein in hypertensive patients

The pathogenesis of essential hypertension through the interaction with elements of the rennin angiotensin aldosterone system is affected by oxidative stress and inflammation. The present study aimed to assess the effects of ACE-Inhibitor, lisinopril, on blood pressure, lipid profiles (total cholesterol, triglycerides, LDL and HDL), MDA, and TAS, hsCRP, and serum leptin levels n hypertensive patients. A case control study included 100 newly diagnosed mild to moderate hypertensive patients and another 100 apparently healthy aged and sex matched subjects as controls. The patients were treated with 10 mg lisinopril orally per day for three months’ duration. Venous blood sample was taken to test levels of MDA, GSH and TAS, hsCRP, lipid profiles and leptin in the serum before and after lisinopril therapy for both patients and controls. Systolic and diastolic blood pressure were also assessed before and after lisinopril therapy for both patients and controls. In hypertensive patients treated with lisinopril, markers of oxidative stress (MDA, TAS and GSH), high sensitive C-reactive protein and leptin were all found to be decreased significantly after drug treatment (p < 0.01). Lisinopril affectively lowered systolic and diastolic BP values (p < 0.01). A significant decrease in lipid profile (p < 0.01) with a significant increase in HDL-C and TAS levels (p < 0.01) were found in lisinopril treated group in comparison with their values before treatment. Lisinopril may be used as a treatment for high blood pressure, as well as for the insulin resistance, hyperleptinemic, and low-grade inflammatory states that are associated with the disease.

Unravelling the Genetic Basis of ACTH-Mediated Aldosterone Hypersecretion in Hypertensive Patients Without Primary Aldosteronism

Introduction: Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. PA includes both sporadic and familial forms, inherited in an autosomal dominant manner. Recent evidence suggests a higher prevalence of aldosterone excess among hypertensive patients than previously thought, while chronic stress-related ACTH-mediated aldosterone hypersecretion has also been implicated in the pathogenesis of essential hypertension. Objective: To determine whether genetic variations of aldosterone regulating genes could be implicated in the ACTH-mediated aldosterone hypersecretion in hypertensive patients without PA. Methods: Twenty-one hypertensive patients without PA, who exhibited ACTH-mediated aldosterone hypersecretion, underwent Whole Exome Sequencing (WES) on Novaseq 6000 platform (Illumina). As hyper-responders were defined patients whose aldosterone (ALD) and aldosterone-to-renin ratio (ARR) response to ultra-low ACTH stimulation test was above the 97.5th percentile values of controls. The cutoff levels for ALD and ARR were 1300 pmol/L and 77 pmol/mIU, respectively. Variant calling was performed according to GATK best practices and VCF files were filtered for variants in 25 genes associated with PA. To identify new susceptibility genes for PA, VCF files were also intersected for variants in ion channels encoding genes involved in pathways responsible for PA. The analysis was restricted to rare variants with gnomAD frequency < 1%. Qualifying variants and pathogenicity were established by employing in silico tools. Copy Number Variant analysis was performed using ExomeDepth algorithm. Results: Eight out of twenty-one patients were heterozygous for rare variants in genes associated with PA, while two patients carried potentially damaging variants in genes encoding ion channels. Specifically, one patient was heterozygous for p.V259M in KCNK5 and one patient was heterozygous for the novel variant p.V221M in KCNK9. Two additional patients carried a predicted pathogenic variant p.R492W in SLC26A2, a gene that has been associated with PA through GWAS. Germline variants in calcium channel genes were also detected in three patients: p.V249I in CACNA1H, p.R462Q in CACNA1D and p.L1801M in CACNA1I, while one patient carried an ultra-rare variant (p.R26L) in ATP13A3. Finally, in two patients we identified rare, likely pathogenic variants in two new susceptibility genes for PA: KCNK16 (p.P255H) and CACNA2D3 (p.V55I). Conclusion: These findings support the notion that mutations in aldosterone synthesis/secretion regulating genes may sensitize zone glomerulosa cells to ACTH stimulation, leading to aldosterone hypersecretion under conditions of stress. We also report two novel candidate susceptibility genes for PA, KCNK16 and CACNA2D3, and one novel variant in KCNK9.

Toll-Like Receptors in the Pathogenesis of Essential Hypertension. A Forthcoming Immune-Driven Theory in Full Effect.

Essential hypertension (EH) is a highly heterogenous disease with a complex etiology. Recent evidence highlights the significant contribution of subclinical inflammation, triggered and sustained by excessive innate immune system activation in the pathogenesis of the disease. Toll-like receptors (TLRs) have been implied as novel effectors in this inflammatory environment since they can significantly stimulate the production of pro-inflammatory cytokines, the migration and proliferation of smooth muscle cells and the generation of reactive oxygen species (ROS), facilitating a low-intensity inflammatory background that is evident from the very early stages of hypertension. Furthermore, the net result of their activation is oxidative stress, endothelial dysfunction, vascular remodeling, and finally, vascular target organ damage, which forms the pathogenetic basis of EH. Importantly, evidence of augmented TLR expression and activation in hypertension has been documented not only in immune but also in several non-immune cells located in the central nervous system, the kidneys, and the vasculature which form the pathogenetic core systems operating in hypertensive disease. In this review, we will try to highlight the contribution of innate immunity in the pathogenesis of hypertension by clarifying the deleterious role of TLR signaling in promoting inflammation and facilitating hypertensive vascular damage.

The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension.

The kidney plays a dominant role in the pathogenesis of essential hypertension, but the initial pathogenic events in the kidney leading to hypertension are not known. Exposure to mercury has been linked to many diseases including hypertension in epidemiological and experimental studies, so we studied the distribution and prevalence of mercury in the human kidney. Paraffin sections of kidneys were available from 129 people ranging in age from 1 to 104 years who had forensic/coronial autopsies. One individual had injected himself with metallic mercury, the other 128 were from varied clinicopathological backgrounds without known exposure to mercury. Sections were stained for inorganic mercury using autometallography. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used on six samples to confirm the presence of autometallography-detected mercury and to look for other toxic metals. In the 128 people without known mercury exposure, mercury was found in: (1) proximal tubules of the cortex and Henle thin loops of the medulla, in 25% of kidneys (and also in the man who injected himself with mercury), (2) proximal tubules only in 16% of kidneys, and (3) Henle thin loops only in 23% of kidneys. The age-related proportion of people who had any mercury in their kidney was 0% at 1–20 years, 66% at 21–40 years, 77% at 41–60 years, 84% at 61–80 years, and 64% at 81–104 years. LA-ICP-MS confirmed the presence of mercury in samples staining with autometallography and showed cadmium, lead, iron, nickel, and silver in some kidneys. In conclusion, mercury is found commonly in the adult human kidney, where it appears to accumulate in proximal tubules and Henle thin loops until an advanced age. Dysfunctions of both these cortical and medullary regions have been implicated in the pathogenesis of essential hypertension, so these findings suggest that further studies of the effects of mercury on blood pressure are warranted.

Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications.

The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1–D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension.

MicroRNA 21 and microRNA 155 levels in resistant hypertension, and their relationships with aldosterone

Aim MicroRNAs (miRNAs) are non-coding RNA molecules that serve as regulators following gene expression transcription. While studies have investigated the role of miRNAs in the pathogenesis of essential hypertension (HT), very few have considered their place in the pathogenesis of resistant hypertension (RH). The purpose of this study was to investigate levels of miRNA 21 and miRNA 155 in RH and their relationships with aldosterone. Method Thirty-two normotensive patients, 30 newly diagnosed HT patients, and 20 RH patients were included in the study. Patients’ demographic data were recorded, and office blood pressure measurement and 24-h ambulatory blood pressure monitoring (24-h ABPM) were performed. Blood specimens were collected for miRNA 21, miRNA 155 and aldosterone measurement. MiRNA 21 and miRNA 155 levels in the control and patient groups and their relations with other demographic and biochemical parameters were then subjected to analysis. Results No difference was determined in miRNA 155 levels between the groups, but miRNA 21 and aldosterone levels were significantly higher in the RH group (p < 0.001 and <0.05, respectively). At correlation analysis, miRNA 21 exhibited positive correlation with aldosterone, age, office SBP, 24-h ABPM all-day SBP. A 9.6 copy/uL level for miRNA 21 predicted presence or absence of RH with 95% sensitivity and 71% specificity (AUC:0.823, 95% CI (0.72–0.92). Conclusion The study results revealed significantly higher miRNA 21 and aldosterone in RH patients than in healthy individuals and newly diagnosed hypertensives.

Serum macrophage colony-stimulating factor levels in patients with essential hypertension after SARS-CoV-2 infection

Understanding changes in the cytokine-mediated mechanisms in immunopathogenesis of essential hypertension (EH) after COVID-19 poses a pressing scientific issue. SARS-CoV-2 exerts direct effects on macrophages with high probability altering regulatory M-CSF-VEGF-A-IL-34 axis, thereby accounting for change in cytokine-mediated patterns of hypertension progression. Immunopathogenesis of complications after SARS-CoV-2 infection and a role of M-CSF in EH pathogenesis justify study objective – to compare the serum M-CSF and VEGF-A, IL-34 levels in stage II EH patients prior to COVID-19 and one month after recovery to assess modality of altered M-CSF-mediated mechanisms behind hypertension progression. Four groups of patients were stratified depending on EH and clinical characteristics of COVID-19 (without/with pneumonia). Blood sampling was performed one month after COVID-19. The serum M-CSF and VEGF-A, IL-34 level was measured by using enzyme-linked immunosorbent assay. The data were statistically processed by using Stat Soft Statistica 13.5. Comparative analysis of serum M-CSF level in patients with stage II EH prior and after COVID-19 revealed that regardless of clinical course (with/without pneumonia) they were featured with higher levels of M-CSF one month after recovery (p 0.001) vs baseline level. The serum VEGF-A level in patients with stage II EH did not change in papallel with increased M-CSF (458 pg/ml or more) one month after SARS CoV 2 infection. However, M-CSF stimulated rise in serum VEGF-A level and accounted for formation of marked coronary collateral network prior to infection. A relationship between the increased serum M-CSF level (higher than 392 pg/ml) and elevated percentage of COVID-19 with pneumonia in patients with stage II EH prior to the infection might be related to the hypothesis about “a role of dysregulated activation of mononuclear phagocytes in development of lung tissue damage”. The data presented prove scientific and clinical value of assessing a role for M-CSF with respect to altered cytokine-mediated patterns of EH progression after COVID-19 recovery.

4-6THE ASSOCIATION OF DNA METHYLATION OF A-ADDUCIN IN ESSENTIAL HYPERTENSION: A QUALITATIVE SYSTEMATIC REVIEW

Introduction: Essential hypertension (EH) is one of the most common health problems with significant mortality and morbidity in the world. EH is a complex multifactorial disease resulting from both genetic and environmental factors. α-Adducin (ADD1) is one of several genetic markers that have been identified. DNA methylation is defined as the addition of a methyl group to the DNA molecule, which associated with a change in the activity of DNA segment without the affection of its sequence. Method: We comprehensively searched case-control studies about essential hypertension and α-adducin in electronic databases including PubMed, EMBASE, and JSTOR. Results: Those three studies (a total 1203 cases and 1148 controls) results were relatively similar, the ADD1 CpG2-5 methylation level was significantly associated with EH, lower CpG1 methylation level was associated with increased risk of EH in females while lower CpG2-5 methylation was associated with an increased risk of EH in males significantly. Discussion: EH is an age-related chronic condition affecting males more than females. We found that DNA methylation of ADD1 gene was significantly higher in females than in males. Adducin was implicated in the pathogenesis of EH by modulating Na+-K+-ATPase activity. CpG1 methylation can predict EH among females, and CpG2-5 methylation does among males. Conclusion: There was an association of DNA methylation of α-Adducin with essential hypertension.

Bioinformatic Analysis of Gene Expression Profile in Plasma of Hypertensive Patients

Abstract Background To analyze expression profiles of long noncoding RNA (lncRNA) and messenger RNA (mRNA) in patients with essential hypertension (EH) and normotensive adults. Methods The gene chip dataset GSE76845, which was generated from 5 plasma samples from patients with EH and 5 normotensives, was downloaded from the National Biotechnology Information Center Public Data Platform. Each sample (total RNA) was pooled from the total RNA of 3 age- and gender-matched subjects (EH patients or healthy controls). A ClusterProfiler package including gene set enrichment analysis (GSEA) was used to identify differentially expressed genes. The target microRNA and mRNA were predicted by microcode, microDB, microTarBase, and TargetScan databases. Finally, a competing endogenous RNAs (ceRNA) regulatory network was constructed. Results Compared with the healthy control adults, 191 differential lncRNAs (90 upregulated and 101 downregulated) and 1,187 differential mRNAs (533 upregulated and 654 downregulated) were identified in EH patients. GSEA analysis showed that 17 pathways, including ubiquinone and terpenoid-quinone biosynthesis, parathyroid hormone synthesis secretion and action, fatty acid metabolism, and steroid hormone biosynthesis are involved in hypertension. A ceRNA network consisting of 150 nodes and 488 interactive pairs was constructed. Conclusions lncRNA and mRNA profile analysis provides new insight into molecular mechanisms of EH pathogenesis and potential targets for therapeutic interventions.

DNA N6-methyladenine modification in hypertension.

DNA methylation has a role in the pathogenesis of essential hypertension. DNA N6-methyladenine (6mA) modification as a novel adenine methylation exists in human tissues, but whether it plays a role in hypertension development remains unclear. Here, we reported that the global 6mA DNA level in leukocytes was significantly reduced in patients with hypertension and was reversed with successful treatment. Age, systolic blood pressure, and serum total cholesterol and high-density lipoprotein levels were associated with decreased leukocyte 6mA DNA level. Elevated ALKBH1 (AlkB homolog 1), a demethylase of 6mA, level mediated this dynamic change in 6mA level in leukocytes and vascular smooth muscle cells in hypertension mouse and rat models. Knockdown of ALKBH1 suppressed angiotensin II-induced vascular smooth muscle phenotype transformation, proliferation and migration. ALKBH1-6mA directly and negatively regulated hypoxia inducible factor 1 α (HIF1α), which responded to angiotensin II-induced vascular remodeling. Collectively, our results demonstrate a potential epigenetic role for ALKBH1-6mA regulation in hypertension development, diagnosis and treatment.

G protein‐coupled receptor 37L1 participates in epigenetic gene regulation in human renal proximal tubule cells

G protein‐coupled receptors (GPCRs) in the kidney regulate the reabsorption of essential nutrients, ions, and water from the glomerular filtrate. Abnormality in the renal luminal sodium transport plays an important role in the pathogenesis of essential hypertension. There are a growing number of GPCRs and their interacting protein components that are localized on the nuclear membrane or within the nucleus, where they retain their signaling functions. In most cases, nuclear GPCRs are constitutively expressed on the nuclear membrane. The functions of these nuclear GPCRs are not well understood. Recently we showed that G protein‐coupled receptor 37L1 (GPR37L1), expressed on the apical membrane of renal proximal tubules (RPT), regulates luminal sodium transport and blood pressure via modulating NHE3 function. However, the GPR37L1 signaling pathway in the RPT has not been studied. Co‐immunoprecipitation (Co‐IP), combined with mass spectrometry analyses, revealed the association of GPR37L1 with nuclear import proteins: IPO7, IPO8, KPNA2, KPNB1; nuclear export proteins: XPO1 and XPO7; nuclear pore complex proteins: NUP210; kinases involved in signaling: mTOR, PRKDC, IRS4; and a DNA (Cytosine‐5‐)‐Methyltransferase 1 (DNMT1) in the GPR37L1 protein complex. Immunoblot analyses of nuclear preparations from the human RPT cells (hRPTCs) confirmed the presence of GPR37L1 in the nucleus. Confocal fluorescence imaging of hRPTCs expressing GPR37L1 tagged with green fluorescence protein (GPR37L1‐GFP) showed distinct nuclear membrane expression of GPR37L1. Association of GPR37L1 with mTOR, PRKDC, and DNMT1 proteins was confirmed by Co‐IP followed by immunoblot analyses. Overexpression of GPR37L1 in hRPTCs increased the phosphorylation of PI3, and AKT and decreased the expression of DNMT1, and NHE3 promoter methylation. Our data show that GPR37L1 signals via the PI3K/AKT/mTOR pathway to decrease the expression of DNMT1. Decreased DNMT1 function reduces CpG methylation on the NHE3 promoter that in turn increases NHE3 transcription. This is the first report showing the direct role of a nuclear GPCR in the regulation of renal sodium transport through epigenetic gene regulation.Support or Funding InformationR56DK116828: Prasad Konkalmatt