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BioRxiv : the Preprint Server For... Nov 2023Hypertension is caused by a combination of genetic and environmental factors. Angiotensinogen (AGT) is a component of RAAS, that regulates blood pressure. The human...
Hypertension is caused by a combination of genetic and environmental factors. Angiotensinogen (AGT) is a component of RAAS, that regulates blood pressure. The human angiotensinogen (hAGT) gene has -6A/-6G polymorphism and -6A variant is associated with human hypertension. In this study, we have investigated the epigenetic regulation of the hAGT. To understand transcriptional regulation of the hAGT, we have made transgenic animals containing -6A. We show that HS affects DNA methylation and modulates transcriptional regulation of this gene in liver and kidney. High salt (HS) increases hAGT gene expression in -6A TG mice. We have observed that the number of CpG sites in the hAGT promoter is decreased after HS treatment. In the liver, seven CpG sites are methylated whereas after HS treatment, only three CpG sites remain methylated. In the kidney, five CpG sites are methylated, whereas after HS treatment, only three CpG sites remain methylated. These results suggest that HS promotes DNA demethylation and increasing AGT gene expression. RT-PCR and immunoblot analysis show that hAGT gene expression is increased by HS. Chip assay has shown that transcription factors bind strongly after HS treatment. RNA-Seq identified differentially expressed genes, novel target genes associated with hypertension, top canonical pathways, upstream regulators. One of the plausible mechanisms for HS induced up-regulation of the hAGT gene is through IL-6/JAK/STAT3/AGT axis.
PubMed: 38045346
DOI: 10.1101/2023.11.22.568343 -
European Heart Journal. Digital Health Dec 2023Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse...
AIMS
Risk assessment tools are needed for timely identification of patients with heart failure (HF) with reduced ejection fraction (HFrEF) who are at high risk of adverse events. In this study, we aim to derive a small set out of 4210 repeatedly measured proteins, which, along with clinical characteristics and established biomarkers, carry optimal prognostic capacity for adverse events, in patients with HFrEF.
METHODS AND RESULTS
In 382 patients, we performed repeated blood sampling (median follow-up: 2.1 years) and applied an aptamer-based multiplex proteomic approach. We used machine learning to select the optimal set of predictors for the primary endpoint (PEP: composite of cardiovascular death, heart transplantation, left ventricular assist device implantation, and HF hospitalization). The association between repeated measures of selected proteins and PEP was investigated by multivariable joint models. Internal validation (cross-validated -index) and external validation (Henry Ford HF PharmacoGenomic Registry cohort) were performed. Nine proteins were selected in addition to the MAGGIC risk score, N-terminal pro-hormone B-type natriuretic peptide, and troponin T: suppression of tumourigenicity 2, tryptophanyl-tRNA synthetase cytoplasmic, histone H2A Type 3, angiotensinogen, deltex-1, thrombospondin-4, ADAMTS-like protein 2, anthrax toxin receptor 1, and cathepsin D. N-terminal pro-hormone B-type natriuretic peptide and angiotensinogen showed the strongest associations [hazard ratio (95% confidence interval): 1.96 (1.17-3.40) and 0.66 (0.49-0.88), respectively]. The multivariable model yielded a -index of 0.85 upon internal validation and -indices up to 0.80 upon external validation. The -index was higher than that of a model containing established risk factors ( = 0.021).
CONCLUSION
Nine serially measured proteins captured the most essential prognostic information for the occurrence of adverse events in patients with HFrEF, and provided incremental value for HF prognostication beyond established risk factors. These proteins could be used for dynamic, individual risk assessment in a prospective setting. These findings also illustrate the potential value of relatively 'novel' biomarkers for prognostication.
CLINICAL TRIAL REGISTRATION
https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 24.
PubMed: 38045440
DOI: 10.1093/ehjdh/ztad056 -
The effect of hormonal contraceptive therapy on clinical laboratory parameters: a literature review.Clinical Chemistry and Laboratory... Jan 2024Hormonal contraceptives (HC) are widely used among women in reproductive ages. In this review, the effects of HCs on 91 routine chemistry tests, metabolic tests, and... (Review)
Review
Hormonal contraceptives (HC) are widely used among women in reproductive ages. In this review, the effects of HCs on 91 routine chemistry tests, metabolic tests, and tests for liver function, hemostatic system, renal function, hormones, vitamins and minerals were evaluated. Test parameters were differently affected by the dosage, duration, composition of HCs and route of administration. Most studies concerned the effects of combined oral contraceptives (COC) on the metabolic, hemostatic and (sex) steroids test results. Although the majority of the effects were minor, a major increase was seen in angiotensinogen levels (90-375 %) and the concentrations of the binding proteins (SHBG [∼200 %], CBG [∼100 %], TBG [∼90 %], VDBP [∼30 %], and IGFBPs [∼40 %]). Also, there were significant changes in levels of their bound molecules (testosterone, T3, T4, cortisol, vitamin D, IGF1 and GH). Data about the effects of all kinds of HCs on all test results are limited and sometimes inconclusive due to the large variety in HC, administration routes and dosages. Still, it can be concluded that HC use in women mainly stimulates the liver production of binding proteins. All biochemical test results of women using HC should be assessed carefully and unexpected test results should be further evaluated for both methodological and pre-analytical reasons. As HCs change over time, future studies are needed to learn more about the effects of other types, routes and combinations of HCs on clinical chemistry tests.
Topics: Female; Humans; Laboratories, Clinical; Sex Hormone-Binding Globulin; Contraceptives, Oral, Combined; Gonadal Steroid Hormones; Testosterone; Carrier Proteins; Hemostatics
PubMed: 37419659
DOI: 10.1515/cclm-2023-0384 -
Frontiers in Pediatrics 2023Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the... (Review)
Review
Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.
PubMed: 38027263
DOI: 10.3389/fped.2023.1274435 -
PeerJ 2023Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive...
BACKGROUND
Thyroid-associated orbitopathy (TAO) is a disease associated with autoimmune thyroid disorders and it can lead to proptosis, diplopia, and vision-threatening compressive optic neuropathy. To comprehensively understand the molecular mechanisms underlying orbital adipogenesis in TAO, we characterize the intrinsic molecular properties of orbital adipose/connective tissue from patients with TAO and control individuals.
METHODS
RNA sequencing analysis (RNA-seq) was performed to measure the gene expression of orbital adipose/connective tissues of TAO patients. Differentially expressed genes (DEGs) were detected and analyzed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Gene Set Enrichment Analysis (GSEA). The protein-protein interaction (PPI) network was constructed using the STRING database, and hub genes were identified by the Cytoscape plug-in, cytoHubba. We validated several top DEGs through quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS
We identified 183 DEGs in adipose tissue between TAO patients ( = 3) and control patients ( = 3) through RNA sequencing, including 114 upregulated genes and 69 downregulated genes. The PPI network of these DEGs had 202 nodes and 743 edges. PCR-based validation results of orbital adipose tissue showed multiple top-ranked genes in TAO patients ( = 4) are immune and inflammatory response genes compared with the control individual ( = 4). They include ceruloplasmin isoform x3 (CP), alkaline tissue-nonspecific isozyme isoform x1 (ALPL), and angiotensinogen (AGT), which were overrepresented by 2.27- to 6.40-fold. Meanwhile, protein mab-21-like 1 (MAB21L1), phosphoinositide 3-kinase gamma-subunit (PIK3C2G), and clavesin-2 (CLVS2) decreased by 2.6% to 32.8%. R-spondin 1 (RSPO1), which is related to oogonia differentiation and developmental angiogenesis, was significantly downregulated in the orbital muscle tissues of patients with TAO compared with the control groups ( = 0.024).
CONCLUSIONS
Our results suggest that there are genetic differences in orbital adipose-connective tissues derived from TAO patients. The upregulation of the inflammatory response in orbital fat of TAO may be consistent with the clinical phenotype like eyelid edema, exophthalmos, and excess tearing. Downregulation of MAB21L1, PIK3C2G, and CLVS2 in TAO tissue demonstrates dysregulation of differentiation, oxidative stress, and developmental pathways.
Topics: Humans; Graves Ophthalmopathy; Phosphatidylinositol 3-Kinases; Connective Tissue; Real-Time Polymerase Chain Reaction; Protein Isoforms; Homeodomain Proteins
PubMed: 38130930
DOI: 10.7717/peerj.16569 -
Risk Management and Healthcare Policy 2023The renin-angiotensin system plays an important role in the central regulation of blood pressure (BP). Genetic variations of angiotensinogen (AGT) and angiotensin II...
PURPOSE
The renin-angiotensin system plays an important role in the central regulation of blood pressure (BP). Genetic variations of angiotensinogen (AGT) and angiotensin II type 1 receptor (AGTR1) may increase susceptibility to elevated BP and hypertension. This study investigated the effects of AGT rs699 and AGTR1 rs5186 single nucleotide polymorphisms (SNPs) on BP at baseline and at a 5-year follow-up.
PATICIPANTS AND METHODS
The study population consisted of participants from the Electricity Generating Authority of Thailand cohort study (n=354); data were collected at baseline (2013) and 5 years later (2018). Genotyping of the two SNPs was performed using TaqMan assay and statistical analyses were performed with SNPStats software.
RESULTS
The frequencies of the two SNPs were within the Hardy-Weinberg equilibrium (p=0.22 for AGT rs699 and p=0.06 for AGTR1 rs5186). For each SNP, mutant genotypes were significantly associated with increased systolic BP and/or diastolic BP in the codominant and recessive models. Risk alleles of AGT rs699 and AGTR1 rs5186 were associated with increased odds of hypertension and hypertension with metabolic syndrome at follow-up.
CONCLUSION
Overall, our results suggest that polymorphisms of genes in the renin-angiotensin system increase susceptibility to the development and progression of hypertension and the development of the metabolic syndrome.
PubMed: 38164294
DOI: 10.2147/RMHP.S442983 -
Counteracting Angiotensinogen Small-Interfering RNA-Mediated Antihypertensive Effects With REVERSIR.Hypertension (Dallas, Tex. : 1979) Jul 2024Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may...
BACKGROUND
Small-interfering RNA (siRNA) targeting hepatic AGT (angiotensinogen) mRNA depletes AGT, lowering blood pressure for up to 6 months. However, certain situations may require a rapid angiotensin increase. The REVERSIR (RVR) - reverse siRNA silencing technology a potential approach to counteract siRNA effects.
METHODS
Spontaneously hypertensive rats received 10 mg/kg AGT siRNA, and 3 weeks later were given AGT-RVR (1, 10, or 20 mg/kg). One week after AGT-RVR dosing, a redose of AGT siRNA assessed its post-AGT-RVR effectiveness for 2 weeks. Additionally, the impact of AGT-RVR after an equihypotensive dose of valsartan (4 mg/kg per day) was examined.
RESULTS
Baseline mean arterial pressure (MAP) was 144±1 mm Hg. AGT siRNA reduced MAP by ≈16 mm Hg and AGT by >95%, while renin increased 25-fold. All AGT-RVR doses restored MAP to baseline within 4 to 7 days. Notably, 10 and 20 mg/kg restored AGT and renin to baseline, while 1 mg/kg allowed ≈50% AGT restoration, with renin remaining above baseline. A second AGT siRNA treatment, following 1 mg/kg AGT-RVR, reduced MAP to the same degree as the initial dose, while following 10 mg/kg AGT-RVR, it resulted in ≈50% of the first dose's MAP effect at 2 weeks. The valsartan-induced MAP reduction was unaffected by AGT-RVR.
CONCLUSIONS
In spontaneously hypertensive rats, angiotensinogen-RVR dose-dependently reversed AGT siRNA-induced AGT reduction, normalizing MAP. MAP normalization persisted even with 50% recovered AGT levels, likely due to upregulated renin maintaining adequate angiotensin generation. Post-AGT-RVR dosing, a second AGT siRNA dose lowered MAP again.
Topics: Animals; Angiotensinogen; RNA, Small Interfering; Rats, Inbred SHR; Rats; Hypertension; Antihypertensive Agents; Male; Blood Pressure; Disease Models, Animal; Valsartan; Renin-Angiotensin System
PubMed: 38690653
DOI: 10.1161/HYPERTENSIONAHA.124.22878 -
Frontiers in Cardiovascular Medicine 2023Whole body manipulation of the renin-angiotensin system (RAS) consistently exerts profound effects on experimental atherosclerosis development. A deficit in the...
BACKGROUND AND OBJECTIVE
Whole body manipulation of the renin-angiotensin system (RAS) consistently exerts profound effects on experimental atherosclerosis development. A deficit in the literature has been a lack of attention to the effects of sex. Also, based on data with gene-deleted mice, the site of RAS activity that influences lesion formation is at an unknown distant location. Since angiotensin (AngII) concentrations are high in kidney and the major components of the RAS are present in renal proximal tubule cells (PTCs), this study evaluated the role of the RAS in PTCs in atherosclerosis development.
METHODS AND RESULTS
Mice with an LDL receptor -/- background were fed Western diet to induce hypercholesterolemia and atherosclerosis. We first demonstrated the role of AT1 receptor antagonism on atherosclerosis in both sexes. Losartan, an AngII type 1 (AT1) receptor blocker, had greater blood pressure-lowering effects in females than males, but equivalent effects between sexes in reducing atherosclerotic lesion size. To determine the roles of renal AT1a receptor and angiotensin-converting enzyme (ACE), either component was deleted in PTCs after weaning using a tamoxifen-inducible Cre expressed under the control of an promoter. Despite profound deletion of AT1a receptor or ACE in PTCs, the absence of either protein did not influence development of atherosclerosis in either sex. Conversely, mice expressing human angiotensinogen and renin in PTCs or expressing human angiotensinogen in liver but human renin in PTCs did not change atherosclerotic lesion size in male mice.
CONCLUSION
Whole-body AT1R inhibition reduced atherosclerosis equivalently in both male and female mice; however, PTC-specific manipulation of the RAS components had no effects on hypercholesterolemia-induced atherosclerosis.
PubMed: 37655218
DOI: 10.3389/fcvm.2023.1250234 -
Frontiers in Endocrinology 2023Hypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin...
INTRODUCTION
Hypertension is a major risk factor for cardiovascular disease (CVD) and is associated with increased bone loss due to excessive activity of the local renin-angiotensin system (RAS). Angiotensinogen/Angiotensin (ANG) II/Angiotensin II type 1 receptor (AT1R) axis is considered as the core axis regulating RAS activity. Azilsartan is an FDA-approved selective AT1R antagonist that is used to treat hypertension. This study aimed to determine whether azilsartan affects formation of osteoclast, resorption of bone, and the expression of cytokines linked with osteoclastogenesis during lipopolysaccharide (LPS)-triggered inflammation .
METHODS
, following a 5-day supracalvarial injection of LPS or tumor necrosis factor-alpha (TNF-α) with or without azilsartan, the proportion of bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, which are identified as osteoclasts on mice calvariae were counted. The mRNA expression levels of TRAP, cathepsin K, receptor activator of NF-κB ligand (RANKL), and TNF-α were also evaluated. , the effect of azilsartan (0, 0.01, 0.1, 1, and 10 μM) on RANKL and TNF-α-triggered osteoclastogenesis were investigated. Also, whether azilsartan restrains LPS-triggered TNF-α mRNA and protein expression in macrophages and RANKL expression in osteoblasts were assessed. Furthermore, western blotting for analysis of mitogen-activated protein kinases (MAPKs) signaling was conducted.
RESULTS
Azilsartan-treated calvariae exhibited significantly lower bone resorption and osteoclastogenesis than those treated with LPS alone. , LPS with azilsartan administration resulted in lower levels of receptor activator of RANKL and TNF-α mRNA expression than LPS administration alone. Nevertheless, azilsartan did not show inhibitory effect on RANKL- and TNF-α-triggered osteoclastogenesis . Compared to macrophages treated with LPS, TNF-α mRNA and protein levels were lower in macrophages treated by LPS with azilsartan. In contrast, RANKL mRNA and protein expression levels in osteoblasts were the same in cells co-treated with azilsartan and LPS and those exposed to LPS only. Furthermore, azilsartan suppressed LPS-triggered MAPKs signaling pathway in macrophages. After 5-day supracalvarial injection, there is no difference between TNF-α injection group and TNF-α with azilsartan injection group.
CONCLUSION
These findings imply that azilsartan prevents LPS-triggered TNF-α production in macrophages, which in turn prevents LPS-Triggered osteoclast formation and bone resorption .
Topics: Animals; Mice; Osteogenesis; Tumor Necrosis Factor-alpha; Lipopolysaccharides; Bone Resorption; Macrophages; Inflammation; Mitogen-Activated Protein Kinases; RNA, Messenger; Hypertension
PubMed: 37795376
DOI: 10.3389/fendo.2023.1207502 -
Saudi Journal of Biological Sciences Sep 2023Cerebrovascular disease is a threat to people with diabetes and hypertension. Diabetes can damage the brain by stimulating the renin-angiotensin system (RAS), leading to...
Cerebrovascular disease is a threat to people with diabetes and hypertension. Diabetes can damage the brain by stimulating the renin-angiotensin system (RAS), leading to neurological deficits and brain strokes. Diabetes-induced components of the RAS, including angiotensin-converting enzyme (ACE), angiotensin-II (Ang-II), and angiotensin type 1 receptor (AT1R), have been linked to various neurological disorders in the brain. In this study, we investigated how diabetes and high blood pressure affected the regulation of these major RAS components in the frontal cortex of the rat brain. We dissected, homogenized, and processed the brain cortex tissues of control, streptozotocin-induced diabetic, spontaneously hypertensive (SHR), and streptozotocin-induced SHR rats for biochemical and Western blot analyses. We found that systolic blood pressure was elevated in SHR rats, but there was no significant difference between SHR and diabetic-SHR rats. In contrast to SHR rats, the heartbeat of diabetic SHR rats was low. Western blot analysis showed that the frontal cortexes of the brain expressed angiotensinogen, AT1R, and MAS receptor. There were no significant differences in angiotensinogen levels across the rat groups. However, the AT1R level was increased in diabetic and hypertensive rats compared to controls, whereas the MAS receptor was downregulated (p < 0.05). These findings suggest that RAS overactivation caused by diabetes may have negative consequences for the brain's cortex, leading to neurodegeneration and cognitive impairment.
PubMed: 37663397
DOI: 10.1016/j.sjbs.2023.103779