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International Journal of Infectious... Jul 2024To analyze the gene variants of the renin-angiotensin-aldosterone system and determine their association with the severity and outcome of COVID-19.
Gene variants rs5182, rs2074192, and rs4343 in the renin-angiotensin-aldosterone system are associated with symptom severity, higher odds of hospitalization, and death in COVID-19.
OBJECTIVES
To analyze the gene variants of the renin-angiotensin-aldosterone system and determine their association with the severity and outcome of COVID-19.
METHODS
A total of 104 patients were included in the study: 34 asymptomatic patients with COVID-19 as controls and 70 symptomatic patients as cases. The genetic variants ACE rs4343, ACE2 rs2074192, AGTR1 rs5182, and AGT rs4762 were identified using TaqMan genotyping tests.
RESULTS
Patients with the T/T genotype of AGTR1 rs5182 have a higher probability of developing symptomatic COVID-19 (odds ratio [OR] 12.25, 95% confidence interval [CI] 1.34-111.9, P ≤0.001) and a higher risk of hospitalization because of disease (OR 14.00, 95% CI 1.53-128.49, P = 0.012). The haplotype CTG (AGTR1 rs5182, ACE2 rs2074192, ACE rs4343) decreased the odds of death related to COVID-19 in the study population (OR 0.03, 95% CI 0.0-0.06, P = 0.026).
CONCLUSIONS
The T/T genotype of the AGTR1 rs5182 variant increased the probability of symptomatic COVID-19 and hospitalization, whereas the haplotype CTG (consisting of AGTR1 rs5182, ACE2 rs2074192, and ACE rs4343) decreased the odds of death related to COVID-19 by 97% in the hospitalized patients with COVID-19. These results support the participation of renin-angiotensin-aldosterone system gene variants as modifiers of the severity of symptoms associated with SARS-CoV-2 infection and the outcome of COVID-19.
Topics: Humans; COVID-19; Male; Female; Hospitalization; Middle Aged; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Angiotensin-Converting Enzyme 2; SARS-CoV-2; Severity of Illness Index; Peptidyl-Dipeptidase A; Adult; Polymorphism, Single Nucleotide; Aged; Angiotensinogen; Genotype; Genetic Predisposition to Disease; Haplotypes; Case-Control Studies
PubMed: 38697603
DOI: 10.1016/j.ijid.2024.107067 -
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 -
Hormones and Behavior Jul 2024Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is...
Alamandine is a peptide hormone belonging to the renin-angiotensin system (RAS). It acts through the Mas-related G-protein coupled receptor type D, MrgD, which is expressed in different tissues, including the brain. In the present study, we hypothesize that a lack of alamandine, through MrgD, could cause the anxiety-like behavior in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)680]. Adult male transgenic rats exhibited a significant increase in the latency to feeding time in the novelty suppressed feeding test and a decrease in the percentage of time and entries in the open arms in the elevated plus maze. These effects were reversed by intracerebroventricular infusion of alamandine. Pretreatment with D-Pro-Ang-(1-7), a Mas and MrgD receptor antagonist, prevented the anxiolytic effects induced by this peptide. However, its effects were not altered by the selective Mas receptor antagonist, A779. In conclusion, our data indicates that alamandine, through MrgD, attenuates anxiety-like behavior in male TGR(ASrAOGEN)680, which reinforces the importance of the counter-regulatory RAS axis as promising target for the treatment of neuropsychiatric disorders.
Topics: Animals; Male; Rats, Transgenic; Receptors, G-Protein-Coupled; Rats; Anxiety; Anti-Anxiety Agents; Angiotensinogen; Brain; Receptors, Gastrointestinal Hormone; Oligopeptides; Nerve Tissue Proteins
PubMed: 38678724
DOI: 10.1016/j.yhbeh.2024.105551 -
MethodsX Jun 2024At present, the numbers of cultured erythroid cells obtained from culture systems are not on a scale that can be used for therapeutics since the cultured erythroid cells...
At present, the numbers of cultured erythroid cells obtained from culture systems are not on a scale that can be used for therapeutics since the cultured erythroid cells have limited proliferation capacity. Stromal cells are believed to play important roles during erythropoiesis. Our previous study shows that factors secreted by stromal cells enhance the proliferation capacity of adult erythroid cells in the culture system. Among the identified factors, angiotensinogen is one of the most abundant proteins secreted by the stromal cells. This study aims to investigate the effect of angiotensin II, an angiotensinogen derivative, on the proliferation of erythroid cells. •The receptor for angiotensin II was first checked by PCR analysis. It was expressed in erythroblasts at all stages during differentiation.•To study the effect of angiotensin II, CD34 hematopoietic stem cells were cultured in a 3-stage erythroid culture system with and without angiotensin II. The addition of angiotensin II to the culture media, from day 0 to 8, significantly increases the numbers of cultured erythroid cells, whereas no difference in enucleation is observed.
PubMed: 38660027
DOI: 10.1016/j.mex.2024.102714 -
Cells Apr 2024Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known...
Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (, , , , , and ) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, , , , and had consistent expressions across samples, while and were lowly expressed. High expression of was independently associated with lower progression-free survival (PFS) ( = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis ( = 0.095). The combined expression of RAS receptors (, , and ) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, and were upregulated after chemoradiotherapy and correlated with an increase in expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes.
Topics: Humans; Renin-Angiotensin System; Up-Regulation; Glioblastoma; Tumor Microenvironment; Receptors, Cell Surface; Prorenin Receptor
PubMed: 38607073
DOI: 10.3390/cells13070634 -
Journal of Pharmacy & Bioallied Sciences Feb 2024Alteration in the various markers is seen in diabetic nephropathy (DN). In the current research, four different markers were evaluated and were examined for their...
INTRODUCTION
Alteration in the various markers is seen in diabetic nephropathy (DN). In the current research, four different markers were evaluated and were examined for their diagnostic value in the nephropathic type 2 diabetes patients.
METHODS
A prospective clinical trial was piloted with diabetic male subjects with nephropathy. The subjects were followed up for 9 months. Thirty subjects were recruited as type 2 diabetes mellitus patients without nephropathy as controls. The interventional groups were grouped again as microalbuminuria, normoalbuminuria, and hyperfiltration. All of them underwent testing for urinary biomarkers like urine protein, ACR, HbA1C, and estimated glomerular filtration rate (eGFR). Correlation and logistic regression were used to compare all diagnostic tests across various groupings.
RESULTS
The greatest area under curve (AUC) values were .90 and .91 for AGT and AGT/Cr, respectively. The AUC, specificity, sensitivity, and cut-off value of AGT/Cr were, respectively, .91, 85%, 91%, and 4.36 mg/g. When using urine as the cut-off, the sensitivity was 42 and 100 for ACR and eGFR both. All other biomarkers had lower values than the AGT. Less than. 50 was evident for NGAL/Cr and NAGL.
CONCLUSIONS
To identify DN, before the initiation of the albuminuria, compared to other diagnostic markers, urinary AGT demonstrated a greater diagnostic value. Further research is suggested to corroborate the findings.
PubMed: 38595634
DOI: 10.4103/jpbs.jpbs_494_23 -
Arteriosclerosis, Thrombosis, and... May 2024AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention... (Review)
Review
AGT (angiotensinogen) is the unique precursor for the generation of all the peptides of the renin-angiotensin system, but it has received relatively scant attention compared to many other renin-angiotensin system components. Focus on AGT has increased recently, particularly with the evolution of drugs to target the synthesis of the protein. AGT is a noninhibitory serpin that has several conserved domains in addition to the angiotensin II sequences at the N terminus. Increased study is needed on the structure-function relationship to resolve many unknowns regarding AGT metabolism. Constitutive whole-body genetic deletion of in mice leads to multiple developmental defects creating a challenge to use these mice for mechanistic studies. This has been overcome by creating -floxed mice to enable the development of cell-specific deficiencies that have provided considerable insight into a range of cardiovascular and associated diseases. This has been augmented by the recent development of pharmacological approaches targeting hepatocytes in humans to promote protracted inhibition of AGT synthesis. Genetic deletion or pharmacological inhibition of has been demonstrated to be beneficial in a spectrum of diseases experimentally, including hypertension, atherosclerosis, aortic and superior mesenteric artery aneurysms, myocardial dysfunction, and hepatic steatosis. This review summarizes the findings of recent studies utilizing AGT manipulation as a therapeutic approach.
Topics: Animals; Humans; Cardiovascular Diseases; Angiotensinogen; Metabolic Diseases; Renin-Angiotensin System; Molecular Targeted Therapy
PubMed: 38572647
DOI: 10.1161/ATVBAHA.124.318374 -
Biochemical Genetics Mar 2024Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if... (Review)
Review
Basal cell carcinoma (BCC) is the most prevalent human neoplasm, with constantly increasing annual incidence. Despite its slow growth, BCC is locally invasive and, if left untreated, can cause severe complications, including metastasis and death. The renin-angiotensin system (RAS) plays a key role in electrolyte balance, atrial pressure, tissue development, homeostasis, and inflammation, but also in cancer development. After binding to its type 1 receptor (AT1R), angiotensin II (ANGII), the system's principal hormonal effector, regulates cancer pathways spanning from the formation of the initial cancer cell to the construction and nutrition of the tumor microenvironment, angiogenesis, proliferation, and metastasis. Although the role of RAS in the development of skin pathologies has not been widely researched, RAS-targeting antihypertensive medications have been shown to have a chemoprotective effect against BCC. Based on those findings, our group conducted a series of genetic association studies to investigate the association between common functional variations in key genes related to ANGII production (AGT, ACE, ACE2, AT1R, AT2R, and CMA1) and the risk of BCC occurrence. This review provides a summary of the current understanding of the ANGII involvement in BCC development. The reliable and easily assessed pool of genetic biomarkers may be used for predictive testing and prevention purposes in high-risk individuals.
PubMed: 38546913
DOI: 10.1007/s10528-024-10746-0 -
Journal of Personalized Medicine Feb 2024Hypertension, characterized by elevated pressure, poses a significant health risk. Recent studies in Jordan highlight high hypertension rates, emphasizing the need for...
BACKGROUND
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 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.
AIMS
This study explores the association between the polymorphism and essential hypertension in Jordan.
METHODS
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 polymorphism was completed using the PCR-RFLP technique. Chi-square and -tests were used for comparisons using SPSS software.
RESULTS
Hypertensive patients exhibited significantly higher weight, BMI, and blood pressure. Genotyping results showed no significant difference ( > 0.05, ) in polymorphism distribution between control and patient groups. In addition, allele frequencies showed comparable patterns ( > 0.05, ). All genotype frequencies showed no deviation from the Hardy-Weinberg equation ( > 0.05, ).
CONCLUSIONS
The 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 genetic polymorphism on the response of antihypertensive drugs among hypertensive patients in Jordan.
PubMed: 38541014
DOI: 10.3390/jpm14030273 -
Frontiers in Pharmacology 2024Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. We developed a novel morphology-based...
Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development. We developed a novel morphology-based screen using organoids from wildtype and (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA). Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in ; LSL- (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal. Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.
PubMed: 38510657
DOI: 10.3389/fphar.2024.1335246