-
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 -
Frontiers in Molecular Biosciences 2023The tumor microenvironment plays a critical role in the radiotherapy and immunotherapy response of cervical squamous cell carcinoma and endocervical adenocarcinoma...
The tumor microenvironment plays a critical role in the radiotherapy and immunotherapy response of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Radioresistance is a key factor in treatment failure among patients who receive radical radiotherapy. Thus, new immune-related biomarkers associated with radiotherapy response in CESC are needed. In this study, the CIBERSORT and ESTIMATE methods were applied to determine the percentage of tumor-infiltrating cells and the number of immune components in 103 CESCs treated with radiotherapy from The Cancer Genome Atlas (TCGA) database. The main dysregulated genes were subjected to multivariate and univariate analyses. The prognostic value of this system was studied via receiver operating characteristic curve and survival analysis. For further confirmation, the biomarkers' expression levels and predictive value were validated by immunohistochemistry (IHC) and qRT-PCR. The CIBERSORT algorithm was used to calculate the compositional patterns of 22 types of immune cells in cervical cancer patients treated with radiation therapy. Data for 17 radioresistant and 86 radiosensitive tumors were obtained from the The Cancer Genome Atlas database. 53 immune-related DEGs were identified. GO and KEGG analyses revealed that the DEGs were enriched in protein kinase B signaling, growth factors in cytokines, the MAPK pathway and the PI3K-Akt pathway. Then, 14 key immune-related genes built a risk scoring model were deemed prognostic in CESC with radiotherapy. The area under the curve (AUC) of the model was 0.723, and the high-risk group presented worse outcomes than the low-risk group. In addition, the high-risk group tended to have persistent tumors ( = 0.001). The high expression of WT1 and SPOUYT4 were associated with relapse, the high expression of Angiotensinogen and MIEN1 were associated with nonrelapse. Analysis of the immune microenvironment indicated that M0 macrophages, M2 macrophages, activated mast cells and resting memory CD4 T cells were positively correlated with the risk score ( < 0.05). The novel immune-related risk scoring system has some advantages in predicting the prognosis and treatment response of cervical cancer patients treated with radiotherapy. Moreover, it might provide novel clues for providing targeted immune therapy to these patients.
PubMed: 38028542
DOI: 10.3389/fmolb.2023.1297774 -
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 -
Kidney International Feb 2024Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested...
Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.
Topics: Humans; Amides; Atypical Hemolytic Uremic Syndrome; Complement Activation; Complement C3; Complement C3-C5 Convertases; Complement Pathway, Alternative; Fumarates; Kidney Diseases; Renin
PubMed: 38008161
DOI: 10.1016/j.kint.2023.11.005 -
Revista Da Associacao Medica Brasileira... 2023The delayed increase in serum creatinine levels poses challenges in the timely diagnosis of acute kidney injury. This study aimed to investigate the relationship between...
OBJECTIVE
The delayed increase in serum creatinine levels poses challenges in the timely diagnosis of acute kidney injury. This study aimed to investigate the relationship between serum angiotensinogen and urinary angiotensinogen levels and the prognosis of renal function in patients diagnosed with acute kidney injury.
METHODS
A total of 79 newly diagnosed acute kidney injury patients aged 18 years and older were enrolled. Serum angiotensinogen and urinary angiotensinogen levels were measured at the onset of the disease, as well as on the 15th and 30th days of follow-up. After 3 months, renal function was evaluated by measuring serum creatinine levels.
RESULTS
Among the acute kidney injury patients, those in Kidney Disease: Improving Global Outcomes stage 3 exhibited significantly higher urinary angiotensinogen/urine creatinine levels compared with stages 1 and 2 patients at the time of diagnosis (p<0.05). Furthermore, a positive correlation was observed between the urinary angiotensinogen/urine creatinine level at the time of diagnosis and the serum creatinine level at the third month (r=0.408, p=0.048).
CONCLUSION
The findings suggest that urinary angiotensinogen levels can serve as an indicator of the severity of acute kidney injury. Monitoring urinary angiotensinogen levels could potentially contribute to the prognosis assessment and management of acute kidney injury patients.
Topics: Humans; Prognosis; Angiotensinogen; Prospective Studies; Creatinine; Biomarkers; Acute Kidney Injury; Kidney
PubMed: 37971126
DOI: 10.1590/1806-9282.20230716 -
Scientific Reports Nov 2023It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen...
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.
Topics: Animals; Gerbillinae; Muscle, Smooth, Vascular; Angiotensinogen; Cholesterol; Hypothyroidism; Aorta; Gene Expression; Myocytes, Smooth Muscle
PubMed: 37951959
DOI: 10.1038/s41598-023-46899-y -
Journal of the... 2023The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality....
Renin Trajectories and Outcome in Stable Heart Failure with Reduced Ejection Fraction (HFrEF) on Contemporary Therapy: A Monocentric Study from an Austrian Tertiary Hospital Outpatient Clinic.
INTRODUCTION
The renin-angiotensin system (RAS) is the main target of neurohumoral therapy in heart failure with reduced ejection fraction (HFrEF) effectively reducing mortality. Reasonably, renin might serve as a biomarker for risk prediction and therapy response. Renin indeed bears some additional value to clinical risk models, albeit the effect is not pronounced. Whether assessing renin trajectories can overcome the weaknesses of single renin measurements has not been reported.
METHODS
A total of 505 patients with stable HFrEF were enrolled prospectively and followed through routine clinical visits. Active plasma renin concentration was documented up to 5 years. Changes in renin were analyzed throughout the disease course, and survival was compared for different renin trajectories within the first year.
RESULTS
Baseline renin levels were not related to all-cause mortality (crude HR for an increase of 100 iE/ml: 1.01 (95% CI: 0.99-1.02), = 0.414) but associated with unplanned HF hospitalizations (crude HR: 1.01 (95% CI: 1.00-1.02), = 0.015). Renin increased during the disease course from baseline to 1-year and 2-year FUP (122.7 vs. 185.6 IU/ml, = 0.039, and 122.7 vs. 258.5 IU/ml, = 0.001). Both survival and unplanned HF hospitalization rates were comparable for different renin trajectories at 1-year FUP ( = 0.546, = 0.357).
CONCLUSIONS
Intriguingly, renin is not a good biomarker to indicate prognosis in HF, while renin trajectories over a 1-year period do not have an additional value. Rapid physiologic plasma renin variations, but also opposing effects of angiotensinogen-derived metabolites under presence of RAS blockade, might obscure the predictive ability of renin.
Topics: Humans; Heart Failure; Renin; Stroke Volume; Austria; Disease Progression; Biomarkers; Hospitalization
PubMed: 37941680
DOI: 10.1155/2023/8883145 -
Arteriosclerosis, Thrombosis, and... Dec 2023Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or... (Review)
Review
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent -acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Topics: Humans; Acetylgalactosamine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Hypertension; Renin; Renin-Angiotensin System; RNA, Small Interfering
PubMed: 37855126
DOI: 10.1161/ATVBAHA.123.319897 -
The Canadian Journal of Infectious... 2023SARS-CoV-2 induces apoptosis and amplifies the immune response by continuously stressing the endoplasmic reticulum (ER) after invading cells. This study aimed to...
BACKGROUND
SARS-CoV-2 induces apoptosis and amplifies the immune response by continuously stressing the endoplasmic reticulum (ER) after invading cells. This study aimed to establish a protein-metabolic pathway associated with ER dysfunction based on the invasion mechanism of SARS-CoV-2.
METHODS
This study included 17 healthy people and 46 COVID-19 patients, including 38 mild patients and 8 severe patients. Proteomics and metabolomics were measured in the patient plasma collected at admission and one week after admission. The patients were further divided into the aggravation and remission groups based on disease progression within one week of admission.
RESULTS
Cross-sectional comparison showed that endoplasmic reticulum molecular chaperone-binding immunoglobulin protein (ERC-BiP), angiotensinogen (AGT), ceramide acid (Cer), and C-reactive protein (CRP) levels were significantly increased in COVID-19 patients, while the sphingomyelin (SM) level was significantly decreased ( < 0.05). In addition, longitudinal comparative analysis found that the temporal fold changes of ERC-BiP, AGT, Cer, CRP, and SM were significantly different between the patients in the aggravation and remission groups ( < 0.05). ERC-BiP, AGT, and Cer levels were significantly increased in aggravation patients, while SM was significantly decreased ( < 0.05). Meanwhile, ERC-BiP was significantly correlated with AGT ( = 0.439; < 0.001).
CONCLUSIONS
ERC-BiP can be used as a core index to reflect the degree of ER stress in COVID-19 patients, which is of great value for evaluating the functional state of cells. A functional pathway for AGT/ERC-BiP/glycolysis can directly assess the activation of unfolded protein reactions. The ERC-BiP pathway is closer to the intracellular replication pathway of SARS-CoV-2 and may help in the development of predictive protocols for COVID-19 exacerbation.
PubMed: 37849973
DOI: 10.1155/2023/7253779 -
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