Angiotensinogen Gene Research Articles

Molecular-Genetic Determinants of Chronic Heart Failure Associated with Type 2 Diabetes and Osteoporosis

This article presents the results of a study on the molecular-genetic factors influencing the development of chronic heart failure (CHF) comorbid with type 2 diabetes mellitus (T2DM) and osteoporosis in postmenopausal women. Polymorphic variants of the IL-1β, eNOS, and angiotensinogen genes were found to be associated with an increased risk of CHF in the presence of T2DM. Alleles and genotypes that can serve as predictors of disease progression were identified. Based on the obtained data, strategies for a personalized approach to the diagnosis and secondary prevention of CHF are proposed. The results emphasize the importance of genetic analysis for improving the prediction of cardiovascular complications and planning therapeutic measures.

Polymorphism of RAAS genes in patients with COVID-19: comparison with frequency in population and relationship with severity of course

Evaluation of genes polymorphisms frequencies of angiotensinogen (AGT), angiotensin converting enzyme type 1 (ACE1) and angiotensin II receptors type 1 (AGTR1) and type 2 (AGTR2) in patients admitted with coronavirus disease (COVID-19) and its association the severity of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2). The study included 100 patients admitted to the hospital with a laboratory-confirmed diagnosis of COVID-19. All patients were identified with alleles and genotypes of polymorphic markers rs4762 of the AGT gene, rs1799752 of the ACE1 gene, rs5186 of the AGTR1 gene and rs1403543 of the AGTR2 gene. The frequencies of each polymorphisms were compared with population. Statistical processing was performed using the Statistica 8.0 software package. In evaluated cohort there was higher frequency of D-allele ACE1 rs1799752 compared to population. Depending on the availability of criteria for the severity of coronavirus infection, 44 (44%) patients were diagnosed with severe, 56 (56%) with moderate course. The groups did not significantly differ in age, gender, cardiovascular risk factors and comorbid pathology. In the groups with severe and moderate course, the same distribution of genotypes and alleles of AGT rs4762, AGTR2 rs1403543 and ACE1 rs1799752 was revealed. For the I/D alleles of the ACE1 rs1799752 gene, a significant deviation from the papulation was found in both the group of severe and moderate COVID-19. In the group with a severe course of the disease, a higher frequency of the mutant C-allele of the AGTR1 rs5186 gene was detected. In the same group, a deviation in the frequency ratio of A and C of the AGTR1 rs5186 alleles from Hardy-Weinberg Equilibrium was found. When calculating the risk of severe COVID-19 in the presence of the C-allele compared with the A-allele, an odds ratio 2.092 (95% confidence interval 1.066-4.108) was obtained. The data obtained suggest that the genes polymorphisms of the components of renin-angiotensin-aldosterone system, namely D-allele of ACE1 rs1799752 and C-allele of AGTR1 rs5186, may make it possible to identify groups of patients predisposed to the development of more severe COVID-19.

Metformin modulates microbiota and improves blood pressure and cardiac remodeling in a rat model of hypertension.

Metformin has been attributed to cardiovascular protection even in the absence of diabetes. Recent observations suggest that metformin influences the gut microbiome. We aimed to investigate the influence of metformin on the gut microbiota and hypertensive target organ damage in hypertensive rats. Male double transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR), a model of angiotensin II-dependent hypertension, were treated with metformin (300 mg/kg/day) or vehicle from 4 to 7 weeks of age. We assessed gut microbiome composition and function using shotgun metagenomic sequencing and measured blood pressure via radiotelemetry. Cardiac and renal organ damage and inflammation were evaluated by echocardiography, histology, and flow cytometry. Metformin treatment increased the production of short-chain fatty acids (SCFA) acetate and propionate in feces without altering microbial composition and diversity. It significantly reduced systolic and diastolic blood pressure and improved cardiac function, as measured by end-diastolic volume, E/A, and stroke volume despite increased cardiac hypertrophy. Metformin reduced cardiac inflammation by lowering macrophage infiltration and shifting macrophage subpopulations towards a less inflammatory phenotype. The observed improvements in blood pressure, cardiac function, and inflammation correlated with fecal SCFA levels in dTGR. Invitro, acetate and propionate altered M1-like gene expression in macrophages, reinforcing anti-inflammatory effects. Metformin did not affect hypertensive renal damage or microvascular structure. Metformin modulated the gut microbiome, increased SCFA production, and ameliorated blood pressure and cardiac remodeling in dTGR. Our findings confirm the protective effects of metformin in the absence of diabetes, highlighting SCFA as a potential mediators.

Renin-Angiotensin System Genes Polymorphisms in Patients With COVID-19 and Its Relation to Severe Cases of SARS-CoV-2 Infection.

Different variants of single nucleotide polymorphisms (SNPs) of angiotensinogen (AGT), angiotensin-converting enzyme type 1 (ACE1), and angiotensin II receptors type 1 (AGTR1) and 2 (AGTR2) genes determine different susceptibility to cardiovascular disease (CVD) and hypertension, which can be considered as risk factors for fatal outcomes among coronavirus disease 2019 (COVID-19) patients. The objective of our study was to assess the relation between the frequency of SNPs of the renin-angiotensin system (RAS) components, and the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The cross-sectional study included 100 patients with a laboratory-confirmed diagnosis of COVID-19 admitted to the hospital. Criteria for severe COVID-19 included respiratory rate (RR) > 30/min, blood oxygen saturation (SpO2) ≤ 93%, signs of unstable hemodynamics with systolic blood pressure (SBP) < 90 and/or diastolic blood pressure (DBP) < 60 mm Hg. All patients were identified with alleles and genotypes of the polymorphic markers rs4762 of the AGT gene, rs1799752 of the ACE1 gene, rs5186 of the AGTR1 gene and rs1403543 of the AGTR2 gene using the polymerase chain reaction method in human DNA preparations on real-time CFX96C1000 Touch, Bio-Rad equipment (Syntol, Russia). Statistical analysis was performed in R v.4.2. Patients were divided into groups with severe (n = 44) and moderate COVID-19 (n = 56). For ACE1 rs1799752, a significant deviation from the population distribution was detected in both studied subgroups. A higher frequency of the C allele SNP rs5186 AGTR1 gene was detected in the group with severe disease. More frequent A/A genotype of SNP rs1403543 AGTR2 was detected among females with severe COVID-19. Haplotype analysis revealed more common DCG haplotype among patients with severe COVID-19. The odds ratio for severe COVID-19 in the presence of the DCG haplotype was 3.996 (95% confidential interval: 1.080 -14.791, P < 0.05). Our data suggest that the SNP genes of the RAS components, may allow to identify groups of patients predisposed to a more severe course of COVID-19.

Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline.

Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).

Identification of immune- and oxidative stress-related signature genes as potential targets for mRNA vaccines for pancreatic cancer patients.

Adenocarcinoma of the pancreas (PAAD) is one of the deadliest malignant tumors, and messenger ribonucleic acid vaccines, which constitute the latest generation of vaccine technology, are expected to lead to new ideas for the treatment of pancreatic cancer. The Cancer Genome Atlas-PAAD and Genotype-Tissue Expression data were merged and analyzed. Weighted gene coexpression network analysis was used to identify gene modules associated with tumor mutational burden among the genes related to both immunity and oxidative stress. Differentially expressed immune-related oxidative stress genes were screened via univariate Cox regression analysis, and these genes were analyzed via nonnegative matrix factorization. After immune infiltration analysis, least absolute shrinkage and selection operator regression combined with Cox regression was used to construct the model, and the usefulness of the model was predicted based on the receiver operating characteristic curve and decision curve analysis curves after model construction. Finally, metabolic pathway enrichment was analyzed using gene set enrichment analysis combined with Kyoto Encyclopedia of Genes and Genomes and gene ontology biological process analyses. This model consisting of the ERAP2, mesenchymal-epithelial transition factor (MET), CXCL9, and angiotensinogen (AGT) genes can be used to help predict the prognosis of pancreatic cancer patients more accurately than existing models. ERAP2 is involved in immune activation and is important in cancer immune evasion. MET binds to hepatocyte growth factor, leading to the dimerization and phosphorylation of c-MET. This activates various signaling pathways, including MAPK and PI3K, to regulate the proliferation, invasion, and migration of cancer cells. CXCL9 overexpression is associated with a poor patient prognosis and reduces the number of CD8 + cytotoxic T lymphocytes in the PAAD tumor microenvironment. AGT is cleaved by the renin enzyme to produce angiotensin 1, and AGT-converting enzyme cleaves angiotensin 1 to produce angiotensin 2. Exposure to AGT-converting enzyme inhibitors after pancreatic cancer diagnosis is associated with improved survival. The 4 genes identified in the present study - ERAP2, MET, CXCL9, and AGT - are expected to serve as targets for messenger ribonucleic acid vaccine development and need to be further investigated in depth.

#2123 Ageing, renal function and frailty: analysis of the FRASNET study

Abstract Background and Aims Frailty is a common geriatric syndrome of significant public health importance. The kidney is one of the organs that progressively loses function with aging leading a decrease of glomerular filtration rate (GFR). In elderly the definition of eGFR threshold for the diagnosis of CKD is debated. FRASNET study aims of identify the role of kidney function (glomerular and tubular involvement) in determining frailty among not community-dwelling elderly adults, also depending on the genetics of each single subject. Method The FRASNET study was a cross-sectional multicentre observational cohort study involving healthy. The exclusion criteria were: i) severe cognitive impairment, ii) severe health problems. They have been characterised for BP, GFR, sodium intake (Kawasaki formula), cognitive status, quality of life, anamnestic factors, health and socio-economic status. Frailty was determined according to modified Fried index by the presence of three conditions among reduced grip strength, reduced gait speed, low physical activity, self-reported exhaustion. We considered the number of drugs as an index of comorbidity. Genotyping of 20 targeted single nucleotide polymorphisms (SNPs) selected on renal and hypertension was performed. ANOVA and conditional inference tree analysis have been carried out. Results 1183 individuals were included in the study sample. Median age was 72 [IQ 69-77]. 328 (27.7%) subjects were robust, 445 (37.6%) pre-frail, 410 (34.7%) frail. Frailty increases with age, especially after 75 years (from 28.9% to 75.7%). The overall mean GFR was 71.8 ± 16.5 ml/min/1.73 m2. Estimated 24 h urinary sodium excretion was 194.5 mEq/24 h with median fractional excretion of sodium (FeNa) 0.75%. In 31.9% of sample FeNa was greater than 1%. Only 3% of subjects reported CKD. Moreover, 21.1% presented eGFR ≤ 60 and the prevalence of CKD increases according to age from 12.3% to 70.3%. CKD prevalence increases in linear manner across frailty classes from 20% in robust to 47.6% in frail. Conditional inference tree analysis confirmed the role of age, comorbidity and GFR in determining frailty. In oldest subjects (&amp;gt;75 years old), the eGFR level most strongly associated with frailty was below 53 (ml/min/1.73 m2) (Fig. 1). No differences in sodium excretion were observed according to frailty classes. Moreover, we observed an increase of FeNa according to age and frailty classes form 0.71% (median (IQR 0.567)) to 0.79% (median (IQR 0.690)). In frail group exaggerated FeNa (&amp;gt;1%) is more frequent than in robust and pre-frail subjects (Chi-squared p = 0.021). Even after the introduction of these variables in inferential trees the new proposed cut-off for GFR (53) is a main determinant of frailty in oldest (Fig. 2). The eGFR parameter resulted associated with two genetic variants in RAAS system, rs5051 in the angiotensinogen gene (AGT) and rs2131127 in the angiotensin II receptor type 1 (AGTR1). The rs4293393 in uromodulin gene (UMOD) was confirmed associated with eGFR value. Conclusion The present study is part of the complex debate on the relationship among renal function, aging and frailty. We can therefore conclude that glomerular filtration (eGFR below 50 and not the presence of CKD) must be considered among the factors that influence frailty. Our study also showed a deterioration of tubular function in frail subject that can be expression of structural changes due to nephroangiosclerosis.

COMBINATION OF TWO DIFFERENT C174T AND C235T OF THE ANGIOTENSINOGEN GENE MUTATION AND C677T METHYLENETETRAHYDROFOLATE REDUCTASE GENE MUTATION IN PATIENTS WITH CVD IN THE POPULATION OF AZERBAIJAN

We studied two mutations of C174T (Met174Tre) and C235T (Met235Tre) of the angiotensinogen gene and mutation C677T (Ala677Val) of the methylenetetrahydrofolate reductase gene, as well as their combinations among patients with cardiovascular diseases: coronary heart disease, myocardial infarction and hypertension, using a complex of modern molecular genetic diagnostic methods. A high frequency of these mutations has been established in the group of patients with severe forms of cardiovascular disorders. Homozygous and compound conditions were found in people with severe diseases. In particular, the heterozygous state of the mutation was found in people with moderate hypertension. It was also found that the presence of close blood relationship between the parents of patients with cardiovascular diseases increases the homozygotization of mutations of the genes AGT and MTGFR in probands. Consequently, such persons are susceptible to the disease or in other words, have an increased risk of developing diseases of the cardiovascular system. For the first time, the frequencies of these mutations in the Azerbaijani population have been determined, which are mostly consistent with the frequencies described in other populations of the world. The studied genetic markers are of interest as genes presumably associated with a wide range of cardiovascular diseases and can be used in further population and epidemiological studies. Therefore, the results of molecular genetic studies obtained by us in people with diseases of the cardiovascular system are of great practical importance. Timely prevention by detecting mutations of C174T, C235T of the AGT gene and C677T of the MTGFR gene in patients will allow doctors to carry out qualified treatment of cardiovascular diseases

No Association Between AGT Gene Polymorphisms with Hypertension in a South African Population.

Hypertension is a leading cause of cardiovascular-related morbidity and mortality worldwide, with a prevalence increasing at an alarming rate in both middle- and low-income countries. Various environmental and genetic factors have been attributed to play a significant role in the increasing prevalence of hypertension. Single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene are reported to have a significant association with hypertension; however, there are limited studies done on South African populations. Therefore, this case-control study aimed to investigate the association between AGT SNPs (rs2004776, rs3789678, rs5051 and rs7079) with hypertension in a study population of isiXhosa-speaking participants from the Eastern Cape Province in South Africa. The SNPs were genotyped in 250 hypertensive cases and 237 normotensive controls, using TaqMan genotyping assays. For the SNP rs2004776, the frequency of CC genotype (18.4%) and C allele (44%) in hypertensive cases showed no significant differences (p = 0.52, χ2 = 1.32), when compared to the normotensive control group (CC: 19.8% and C allele: 43%). Similar results were obtained for the genotypic and allelic frequencies between hypertensive cases and normotensive controls for rs3789678 (p = 0.88, χ2=0.26) and rs5051 (p = 0.57, χ2=1.12), and rs7079 (p = 0.33, χ2=2.23). These findings demonstrate that there were no significant associations between the SNPs rs2004776, rs3789678, rs7079, rs5051 with hypertension in our study population. These findings suggest that AGT gene polymorphisms are not associated with the development of hypertension in the studied population. The present study represents the first genetic report to investigate the AGT gene polymorphisms with hypertension in an isiXhosa-speaking South African population.

The Association of M235T Genetic Polymorphism in Angiotensinogen Gene and Other Non-Genetic Factors with Essential Hypertension among Jordanian Patients.

Hypertension, characterized by elevated pressure, poses a significant health risk. Recent studies in Jordan highlight high hypertension rates, emphasizing the need for genetic investigations to comprehend essential hypertension determinants. The AGT gene, part of the Renin Angiotensin System, is linked to blood pressure regulation. Limited information exists on the frequency of this polymorphism among Jordanian hypertensive patients. This study explores the association between the AGT M235T polymorphism and essential hypertension in Jordan. A cross-sectional study with 435 participants (199 hypertensive, 236 non-hypertensive) was conducted at the University of Jordan Hospital. Blood pressure was measured, and genetic analysis of the AGT M235T polymorphism was completed using the PCR-RFLP technique. Chi-square and t-tests were used for comparisons using SPSS software. Hypertensive patients exhibited significantly higher weight, BMI, and blood pressure. Genotyping results showed no significant difference (p > 0.05, Chi-square) in AGT M235T polymorphism distribution between control and patient groups. In addition, allele frequencies showed comparable patterns (p > 0.05, Chi-square). All genotype frequencies showed no deviation from the Hardy-Weinberg equation (p > 0.05, Chi-square). The AGT M235T genetic polymorphism is not more prevalent among hypertensive patients in Jordan, although the average weight and BMI among hypertensive patients is higher than the non-hypertensive participants. Obesity can be addressed as a potential risk factor for essential hypertension in Jordan. In addition, it is recommended to find out the influence of the AGT M235T genetic polymorphism on the response of antihypertensive drugs among hypertensive patients in Jordan.

Comparison of the effects of renal denervation at early or advanced stages of hypertension on cardiac, renal, and adipose tissue pathology in Dahl salt-sensitive rats

Renal denervation (RDN) has emerged as a novel therapy for drug-resistant hypertension. We here examined the effects of RDN at early versus advanced stages of hypertension on blood pressure and organ pathology in rats with salt-sensitive hypertension. Dahl salt-sensitive (DahlS) rats fed an 8% NaCl diet from 6 weeks of age were subjected to RDN (surgical ablation and application of 10% phenol in ethanol) or sham surgery at 7 (early stage) or 9 (advanced stage) weeks and were studied at 12 weeks. RDN at early or advanced stages resulted in a moderate lowering of blood pressure. Although RDN at neither stage affected left ventricular (LV) and cardiomyocyte hypertrophy, it ameliorated LV diastolic dysfunction, fibrosis, and inflammation at both stages. Intervention at both stages also attenuated renal injury as well as downregulated the expression of angiotensinogen and angiotensin-converting enzyme (ACE) genes and angiotensin II type 1 receptor protein in the kidney. Furthermore, RDN at both stages inhibited proinflammatory gene expression in adipose tissue. The early intervention reduced both visceral fat mass and adipocyte size in association with downregulation of angiotensinogen and ACE gene expression. In contrast, the late intervention increased fat mass without affecting adipocyte size as well as attenuated angiotensinogen and ACE gene expression. Our results thus indicate that RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated cardiac and renal injury and adipose tissue inflammation in DahlS rats. They also suggest that cross talk among the kidney, cardiovascular system, and adipose tissue may contribute to salt-sensitive hypertension.Supposed mechanism for the beneficial effects of RDN on hypertension and target organ damage in DahlS rats. RDN at early or late stages after salt loading moderately alleviated hypertension and substantially ameliorated renal injury in DahlS rats. Cross talk among the kidney, cardiovascular system, and adipose tissue possibly mediated by circulating RAS may contribute to salt-sensitive hypertension. LV; left ventricular, NE; norepinephrine, RAS; renin-angiotensin system, RDN; renal denervation.

Genetic insights into endurance athlete status: A meta-analysis of ACVR1B, AGT, FTO, IL-6, and NRF2 gene polymorphisms.

The aim of this meta-analysis was to analyze allele and genotype pattern frequencies of five different gene polymorphisms associated with endurance athlete status. Endurance sports require prolonged physical performance, and it is well known that physiological and genetic characteristics play a prominent role in this performance. In recent years, research on the impact of genetic factors on endurance athlete status has been on the rise, suggesting that various gene polymorphisms may be associated with physical performance. Specifically, the gene polymorphisms, activin receptor type-1B (A9CVR1B) rs2854464, angiotensinogen (AGT) rs699, fat mass and obesity-associated (FTO) rs9939609, interleukin-6 (IL-6) rs1800795, and nuclear factor erythroid 2 (NRF2) rs12594956, are thought to be related to endurance athlete status. Each of these genes plays a part in different biological processes, such as muscle development, energy metabolism, inflammation, and antioxidant defense mechanisms. For example, the NRF2 gene is a critical player in the regulation of cellular stress responses and may contribute to adaptive responses that enhance performance in endurance athletes. This meta-analysis included a total of 20 articles published between 2009 and 2023. The specific gene polymorphisms explored in this study, i.e., ACVR1B rs2854464, AGT rs699, FTO rs9939609, IL-6 rs1800795, and NRF2 rs12594956, were selected due to their reported associations with physical performance and endurance. A comprehensive search was conducted in the Web of Science and PubMed databases using specific keywords, preliminarily identifying 329 articles. Upon analysis of the abstracts, and full texts, 20 articles were deemed eligible for inclusion in this meta-analysis. Articles lacking control and endurance athlete groups or clear allele/genotype data were excluded. The findings indicated no significant differences in allele and genotype frequencies for ACVR1B, AGT, FTO, and IL-6 gene polymorphisms between endurance athletes and control groups. However, the NRF2 rs12594956 gene polymorphism showed a significantly higher frequency of the major allele (A) and the AA genotype in endurance athletes than in controls. In conclusion, the NRF2 rs12594956 polymorphism may be a genetic variant of interest in determining the status of endurance athletes. These findings highlight the potential clinical implications for genetic screening and personalized training programs in sport genetics. More extensive studies with larger cohorts are needed to further confirm these associations.

Association between plasma angiotensinogen level and response to valsartan among sample of Iraqi hypertensive patients.

Aim: The main aim of the present paper is to investigate allele frequencies of rs1799983 polymorphism eNOS genes and to determine association between rs1799983 polymorphism of eNOS gene and essential hypertension in Iraqi hypertensive patients. Materials and Methods: Data obtained at the Al-Diwaniyah teaching hospital in Iraq by researchers from the Department of Pharmacology and Therapeutics in the College of Medicine at University of Al-Qadisiyah from July 2022 to July 2023. All participants (aged 20 to 70) had been taking valsartan 160 mg once day for essential hypertension for at least two weeks before to the study. There were a total of 90 participants, 37 males and 53 women. Initial investigations of hypertension have indicated that the angiotensinogen gene has a substantial impact in susceptibility to essential hypertension through observational cross sectional descriptive single center study. Results: Indicate, in patients with essential hypertension, that the "AGT gene A>G (rs699) and C>T(rs5051)" have high angiotensinogen level, and there is no signif i cant association between these two (rs699, rs5051) and responsiveness to valsartan (P >0.05). Conclusions: Result showed the most common allele for rs699 was G allele (67%) while the most frequent genotype was AG (49%) and regarding rs5051 the most frequent allele was C (54%) while the most frequent genotype was CT (46%). In this study we demonstrate the lack of signif i cant association between two these polymorphisms and clinical response to valsartan (P >0.05).

The RAAS system SNPs polymorphism is associated with essential hypertension risk in rural areas in northern China.

Objectives: Epidemiological evidence has shown that genetics and environment are associated with the risk of hypertension. However, the specific SNP effects of a cluster of crucial genes in the RAAS system on the risk of hypertension are unclear. Methods: A case-control study was performed on the baseline participants of Environment and Chronic Disease in Rural Areas of Heilongjiang China (ECDRAHC) study. According to the inclusion and exclusion criteria, 757 subjects (428 hypertensive patients) were enrolled. A total of 32 SNP sites and related haplotypes, involved in AGT (angiotensinogen), ACE (angiotensin-converting enzyme), AGTR1, CYP11B2 (aldosterone-synthase), LDLR (low-density lipoprotein receptor), LRP5 (low-density lipoprotein receptor associated protein 5), LRP6 (low-density lipoprotein receptor associated protein 6), PPARG (peroxisome proliferator-activated receptor gamma) and ACE2 (angiotensin-converting enzyme 2) genes which exert important roles in renin-angiotensin-aldosterone system (RAAS) system were analyzed. Furthermore, a polygenic scoring model was established to assess individual risk of developing hypertension based on the comprehensive SNPs effects in genes related the RAAS system. Results: After controlling the impact of confounding factors, multivariate logistic regression analysis revealed that the distribution of AGT/rs5046, LRP6/rs12823243 and ACE2/rs2285666 was associated with susceptibility to essential hypertension. In genetic score model, the score > -0.225 had a higher risk, the OR (95%CI) was 1.229 (1.110, 1.362). Conclusions: To the best of our knowledge, this is the first time a hypertension risk scoring model on RAAS associated gene cluster has been constructed, which will provide a novel approach for prevention and control of essential hypertension.

Взаимосвязь полиморфизмов генов ренин-ангиотензиновой системы с показателями интенсивности кариеса зубов

When it comes to studying periodontal diseases and their correlation with general physical pathology, the relationship between the state of oral organs and tissues and the haemodynamic system is of interest; however, research is often conducted without taking into account molecular genetic determinants. The purpose of this article was to determine the relationship of the T704C and C521C polymorphisms of the angiotensinogen (AGT) gene and A1166C polymorphism of the angiotensin II receptor type 1 (AGT2R1) gene with dental caries experience in young people living in the European North of Russa. Materials and methods. The research included 57 healthy male and female subjects (mean age 18.2 years; confidence interval 17.9–19.4) permanently residing in the Arkhangelsk Region. The polymorphisms under study were genotyped by means of pyrosequencing; their allele and genotype frequencies were determined. Angiotensin II level in blood plasma was measured using enzyme-linked immunosorbent assay. Decay-missing-filled (DMF) index and forms of caries in subjects with and without mutant alleles for each gene variant were determined. Results. Young individuals with mutant AGT and AGT2R1 gene alleles showed high DMF index; however, a statistically significant increase in DMF index was observed only in the case of the T704C polymorphism. Angiotensin II levels in young subjects did not differ statistically significantly by sex; however, a tendency was observed towards increased angiotensin II level in the presence of mutant alleles of all the genes under study in the genotype. Among the carriers of the mutant C allele of the T704C polymorphism of the AGT gene, subjects with the decompensated form of caries prevailed, while carriers of the mutant T allele of the C521T polymorphism of the AGT gene showed higher frequency of the subcompensated form of caries. Carriers of the mutant C allele of the A1166C polymorphism of the AGT2R1 gene demonstrated increased frequency of the compensated form of caries with a slight decrease in the frequency of the subcompensated and decompensated forms.

Enlighten the association of Angiotensinogen gene (AGT) polymorphisms and hypertension in Jammu region of north Indian population: A case-control study

BackgroundHypertension is a common cause associated with various life-threatening disorders such as stroke, heart attack, etc. AGT, with its two common polymorphisms, i.e., rs699 and rs4762, has been associated with variation in plasma angiotensinogen concentration and linked to essential hypertension. AimIn the present study, we aimed to find the association between the two polymorphisms, namely rs699 and rs4762 of the AGT gene, with the risk of hypertension in people of the Jammu region of Jammu and Kashmir. MethodTo achieve the aim, an observational with case-control study design was utilized where the descriptive and inferential data were presented in frequency, and an Odds ratio with a 95% Confidence Interval was used for determining the risk association, respectively. Online free statistical tools were used for the statistical analysis. The pairwise linkage disequilibrium (LD) and its respective measures (D′ & r(Mills et al., 2020 (Mills et al., 2020))) for the SNPs among the hypertensive patients and controls were calculated using Haploview software. ResultA total of 180 cases and 350 controls were enrolled, where “rs699” showed an increased risk (OR: 1.72 [1.28–2.31], p-value =0.0003) for hypertension in contrast to “rs4762” which showed a protective role (OR: 0.55 [0.37–0.82], p-value <0.002) in the population of Jammu. After linkage disequilibrium analysis, the risk of disease due to haplotype was also analyzed, and it was found that CC (rs699/ rs4762) significantly (p-value <0.00001) increases the risk by 1.9-fold. ConclusionThe present study concluded that “rs699” showed an increased risk for hypertension in the population of the Jammu region in contrast to “rs4762”.

Hypothyroidism increases angiotensinogen gene expression associated with vascular smooth muscle cells cholesterol metabolism dysfunction and aorta remodeling in Psammomys obesus

It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen (Agt) and vascular smooth muscle cells (VSMCs) dysfunction in the pathophysiology of cardiovascular manifestations in hypothyroidism have not yet been investigated. We induced experimental hypothyroidism in Psammomys obesus by administering carbimazole for five months. At the end of the experiment, the animals were sacrificed and histopathological analysis was performed using Masson's trichrome staining of the aorta and thyroid gland. The expression of the Agt gene and the genes implicated in cholesterol metabolism regulation in the liver and VSMCs was determined by qRT-PCR. Histological observations revealed profound remodeling of the aorta structure in animals with hypothyroidism. In addition, Agt gene expression in the liver was significantly increased. In vitro study, showed that VSMCs from hypothyroid animals overexpressed 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and Acyl CoA:cholesterol acyltransferase (Acat) 1, with failure to increase the efflux pathway genes (ATP-binding cassette subfamily G member (Abcg) 1 and 4). These results suggest that hypothyroidism leads to vascular alterations, including structural remodeling, VSMCs cholesterol metabolism dysfunction, and their switch to a synthetic phenotype, together with hepatic Agt gene overexpression.

Genetic aspects of predicting the results of treatment of patients with atherosclerosis of the arteries of the lower extremities

Relevance. The reasons for the unsatisfactory results of treatment of atherosclerotic diseases of the arteries of the lower extremities are associated not only with the limited possibilities of conservative and operative methods of treatment, but also with the lack of objective criteria that allow predicting the course of this pathology and the effectiveness of planned therapeutic measures. The purpose of the study. Improving the results of treatment of patients with atherosclerosis of the arteries of the lower extremities on the basis of predicting the effectiveness of conservative and surgical treatment, taking into account genetic polymorphism. Materials and methods. The results of treatment and specially conducted studies were analyzed in 226 patients with atherosclerosis of the arteries of the lower extremities aged 40 to 89 years. The median age was 66.7 years. There were 157 males (69.5%) and 69 females (30.5%). Standard research methods were aimed at determining the biochemical status and assessing the state of arterial blood flow of patients. Genetic studies of 17 genes in the blood serum of patients were carried out using the polymerase chain reaction method. Results. It was revealed that the genes encoding elements of the renin-angiotensin-aldosterone system (angiotensinogen genes AGT:704 and AGT:521, angiotensin II receptor AGTR1:1166 and AGTR2:1675, aldosterone synthetase CYP11B2) have clinical significance; genes regulating intracellular ion homeostasis (G protein beta-3 subunit GNB3, alpha-adductin ADD1:1378); genes determining the structure of endothelial NO synthase (NOS3:894 and NOS3:786); hemostasis genes (F5 Leiden factor, prothrombin F2, plasminogen activator inhibitor PAI-1, platelet receptor fibrinogen GPIIIA, fibrinogen FGB); cytochrome P-450 CYP2D6 and CYP2C9 genes; genes of glycoprotein P MDR1. The dependence of gene polymorphism on the level of occlusion and the stage of the disease has been established. In order to determine the possibilities of predicting the effectiveness of therapeutic measures, a comparative assessment of the indicators of genetic testing was carried out, depending on the result of conservative therapy and surgical treatment. Conclusions. Genetic polymorphism determines the progression of obliterating atherosclerosis of the arteries of the lower extremities and is associated with the effectiveness of conservative and surgical therapeutic measures. The use of genetic testing using methods of multidimensional statistics makes it possible to predict the effectiveness of reconstructive operations in patients with chronic lower limb ischemia, taking into account not only clinical, laboratory and instrumental data, but also on the basis of changes in gene polymorphism.

Increased CaMKII activation and contrast changes of cardiac β1-and β3-Adrenergic signaling pathways in a humanized angiotensinogen model of hypertension

AimsUpregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) contributes to the pathogenesis of cardiovascular disease, including hypertension. Transgenic rats expressing the human angiotensinogen gene [TGR (hAGT)L1623] are a new novel humanized model of hypertension that associates with declines in cardiac contractile function and β-adrenergic receptor (AR) reserve. The molecular mechanisms are unclear. We tested the hypothesis that in TGR (hAGT)L1623 rats, left ventricular (LV) myocyte CaMKIIδ and β3-AR are upregulated, but β1-AR is down-regulated, which are important causes of cardiac dysfunction and β-AR desensitization. Main methodsWe compared LV myocyte CaMKIIδ, CaMKIIδ phosphorylation (at Thr287) (pCaMKIIδ), and β1-and β3-AR expressions and determined myocyte functional and [Ca2+]I transient ([Ca2+]iT) responses to β-AR stimulation with and without pretreatment of myocytes using an inhibitor of CaMKII, KN-93 (10−6 M, 30 min) in male Sprague Dawley (SD; N = 10) control and TGR (hAGT)L1623 (N = 10) adult rats. Key findingsHypertension in TGR (hAGT)L1623 rats was accompanied by significantly increased LV myocyte β3-AR protein levels and reduced β1-AR protein levels. CaMKIIδ phosphorylation (at Thr287), pCaMKIIδ was significantly increased by 35%. These changes were followed by significantly reduced basal cell contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca2+]iT. Isoproterenol (10−8 M) produced significantly smaller increases in dL/dtmax, dR/dtmax, and [Ca2+]iT. Moreover, only in TGR (hAGT)L1623 rats, pretreatment of LV myocytes with KN-93 (10−6 M, 30 min) fully restored normal basal and isoproterenol-stimulated myocyte contraction, relaxation, and [Ca2+]iT. SignificanceLV myocyte CaMKIIδ overactivation with associated contrast changes in β3-AR and β1-AR may be the key molecular mechanism for the abnormal contractile phenotype and β-AR desensitization in this humanized model of hypertension.

Sodium appetite and thirst do not require angiotensinogen production in astrocytes or hepatocytes.

In addition to its renal and cardiovascular functions, angiotensin signaling is thought to be responsible for the increases in salt and water intake caused by hypovolemia. However, it remains unclear whether these behaviors require angiotensin production in the brain or liver. Here, we use in situ hybridization to identify tissue-specific expression of the genes required for producing angiotensin peptides, then use conditional genetic deletion of angiotensinogen (Agt) to test whether production in the brain or liver is necessary for sodium appetite and thirst. In the mouse brain, we identified expression of Agt (the precursor of all angiotensin peptides) in a large subset of astrocytes. We also identified Ren1 and Ace (enzymes required to produce angiotensin II) in the choroid plexus, and Ren1 in neurons within the nucleus ambiguus compact formation. In the liver, we confirmed that Agt is expressed in widespread hepatocytes. We next tested whether thirst and sodium appetite require angiotensinogen production in astrocytes or hepatocytes. Despite virtually eliminating expression in the brain, deleting astrocytic Agt did not reduce thirst or sodium appetite. Despite markedly reducing angiotensinogen in the blood, eliminating Agt from hepatocytes did not reduce thirst or sodium appetite, and in fact, these mice consumed the largest amounts of salt and water after sodium deprivation. Deleting Agt from both astrocytes and hepatocytes also did not prevent thirst or sodium appetite. Our findings suggest that angiotensin signaling is not required for sodium appetite or thirst and highlight the need to identify alternative signaling mechanisms. KEY POINTS: Angiotensin signaling is thought to be responsible for the increased thirst and sodium appetite caused by hypovolemia, producing elevated water and sodium intake. Specific cells in separate brain regions express the three genes needed to produce angiotensin peptides, but brain-specific deletion of the angiotensinogen gene (Agt), which encodes the lone precursor for all angiotensin peptides, did not reduce thirst or sodium appetite. Double-deletion of Agt from brain and liver also did not reduce thirst or sodium appetite. Liver-specific deletion of Agt reduced circulating angiotensinogen levels without reducing thirst or sodium appetite. Instead, these angiotensin-deficient mice exhibited an enhanced sodium appetite. Because the physiologic mechanisms controlling thirst and sodium appetite continued functioning without angiotensin production in the brain and liver, understanding these mechanisms requires a renewed search for the hypovolemic signals necessary for activating each behavior. Abstract figure legend Angiotensinogen is the precursor for angiotensin II, which is considered important for thirst and sodium appetite. In the brain, astrocytes express the angiotensinogen gene (Agt), but using GFAP-Cre to delete this gene from astrocytes did not reduce thirst or sodium appetite. In the liver, hepatocytes express this gene and produce circulating angiotensinogen. Using Alb-Cre to delete Agt from hepatocytes also did not reduce (and in fact enhanced) salt and water consumption. This article is protected by copyright. All rights reserved.