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BioRxiv : the Preprint Server For... May 2023Hepatic knockdown of the proprotein convertase subtilisin/kexin type 9 ( ) gene or the angiopoietin-like 3 ( ) gene has been demonstrated to reduce blood low-density...
BACKGROUND
Hepatic knockdown of the proprotein convertase subtilisin/kexin type 9 ( ) gene or the angiopoietin-like 3 ( ) gene has been demonstrated to reduce blood low-density lipoprotein cholesterol (LDL-C) levels, and hepatic knockdown of the angiotensinogen ( ) gene has been demonstrated to reduce blood pressure. Genome editing can productively target each of these three genes in hepatocytes in the liver, offering the possibility of durable "one-and-done" therapies for hypercholesterolemia and hypertension. However, concerns around making permanent gene sequence changes via DNA strand breaks might hinder acceptance of these therapies. Epigenome editing offers an alternative approach to gene inactivation, via silencing of gene expression by methylation of the promoter region, but the long-term durability of epigenome editing remains to be established.
METHODS
We assessed the ability of epigenome editing to durably reduce the expression of the human , and genes in HuH-7 hepatoma cells. Using the CRISPRoff epigenome editor, we identified guide RNAs that produced efficient gene knockdown immediately after transfection. We assessed the durability of gene expression and methylation changes through serial cell passages.
RESULTS
Cells treated with CRISPRoff and guide RNAs were maintained for up to 124 cell doublings and demonstrated durable knockdown of gene expression and increased CpG dinucleotide methylation in the promoter, exon 1, and intron 1 regions. In contrast, cells treated with CRISPRoff and guide RNAs experienced only transient knockdown of gene expression. Cells treated with CRISPRoff and guide RNAs also experienced transient knockdown of gene expression; although initially there was increased CpG methylation throughout the early part of the gene, this methylation was geographically heterogeneous-transient in the promoter, and stable in intron 1.
CONCLUSIONS
This work demonstrates precise and durable gene regulation via methylation, supporting a new therapeutic approach for protection against cardiovascular disease via knockdown of genes such as . However, the durability of knockdown with methylation changes is not generalizable across target genes, likely limiting the therapeutic potential of epigenome editing compared to other modalities.
PubMed: 37292627
DOI: 10.1101/2023.05.17.541156 -
Anatolian Journal of Cardiology Jul 2023Activation of the reninangi otens in-aldosterone system has an important role in the pathophysiology of heart failure with reduced ejection fraction. While the effects...
BACKGROUND
Activation of the reninangi otens in-aldosterone system has an important role in the pathophysiology of heart failure with reduced ejection fraction. While the effects of systemic reninangi otens in-aldosterone system activation on heart failure with reduced ejection fraction are well known, the impact of the local reninangi otens in-aldosterone system on heart failure with reduced ejection fraction is not fully understood because of limited clinical research. This study aimed to investigate the effect of urinary angiotensinogen level, an accepted indicator of local reninangi otens in-aldosterone system activation, on all-cause mortality in patients with heart failure with reduced ejection fraction.
METHODS
This retrospective, single-center study included 60 patients with baseline urinary angiotensinogen data and survival/mortality data at 4 years. Urinary angiotensinogen values were standardized to the urinary creatinine value measured from the same urine sample. The median urinary angio tensi nogen /urin ary creatinine value among all patients (114 μg/g) was used as a cutoff to divide the patients into 2 groups. Mortality data were obtained from the national registry systems or by telephone.
RESULTS
Comparison of all-cause mortality in the 2 groups showed that 22 deaths (71%) occurred in the group with a urinary angio tensinogen/urinary creatinine ratio above the median and 10 deaths (35.5%) occurred in the group of patients with urinary angio tensinogen/urinary creatinine equal to or below the median value (P =.005).
CONCLUSION
Our study suggests that urinary angiotensinogen can be used as a new biomarker in the prognosis and follow-up of heart failure patients.
Topics: Humans; Angiotensinogen; Renin-Angiotensin System; Aldosterone; Creatinine; Stroke Volume; Retrospective Studies; Heart Failure; Prognosis
PubMed: 37288852
DOI: 10.14744/AnatolJCardiol.2023.2719 -
Hypertension Research : Official... Aug 2023Preeclampsia is a hypertensive disorder in pregnancy characterized by placental malperfusion and subsequent multi-organ injury. It accounts for approximately 14% of... (Review)
Review
Preeclampsia is a hypertensive disorder in pregnancy characterized by placental malperfusion and subsequent multi-organ injury. It accounts for approximately 14% of maternal deaths and 10-25% of perinatal deaths globally. In addition, preeclampsia has been attracting attentions for its association with risks for developing chronic diseases in later life for both mother and child. This mini-review discusses on latest knowledge on prediction, prevention, management, and long-term outcomes of preeclampsia and also touches on association between COVID-19 and preeclampsia. HTN hypertension, HDP hypertensive disorders of pregnancy, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, VEGF vascular endothelial growth factor, VEGFR VEGF receptor, TGFβ transforming growth factor β, ENG endoglin, sENG soluble ENG, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, CVD cardiovascular disease, ESKD end-stage kidney disease, ACE angiotensinogen converting enzyme, Ang angiotensin.
Topics: Female; Humans; Pregnancy; Biomarkers; COVID-19; Endoglin; Hypertension; Placenta; Placenta Growth Factor; Posterior Leukoencephalopathy Syndrome; Pre-Eclampsia; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 37268721
DOI: 10.1038/s41440-023-01323-w -
Experimental & Molecular Medicine Jun 2023The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the...
The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers.
Topics: Carcinogens; Nicotiana; Nitrosamines; Receptors, Nicotinic; Renin-Angiotensin System; STAT3 Transcription Factor; Lung Neoplasms; Signal Transduction; Lung; Carcinogenesis
PubMed: 37258578
DOI: 10.1038/s12276-023-00994-2 -
Biomedicine & Pharmacotherapy =... Aug 2023High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen...
High-fat diet (HFD)-induced obesity is a cause of resistant hypertension. We have shown a possible link between histone deacetylases (HDACs) and renal angiotensinogen (Agt) upregulation in the HFD-induced hypertension, whereas the underlying mechanisms remain to be elucidated. Here, using a HDAC1/2 inhibitor romidepsin (FK228) and siRNAs, we determined roles of HDAC1 and HDAC2 in HFD-induced hypertension and found the pathologic signaling axis between HDAC1 and Agt transcription. Treatment with FK228 canceled the increased blood pressure of male C57BL/6 mice induced by HFD. FK228 also blocked upregulation of renal Agt mRNA, protein, angiotensin II (Ang II) or serum Ang II. Activation and nuclear accumulation of both HDAC1 and HDAC2 occurred in the HFD group. The HFD-induced HDAC activation was associated with an increase in deacetylated c-Myc transcription factor. Silencing of HDAC1, HDAC2 or c-Myc in HRPTEpi cells decreased Agt expression. However, only HDAC1 knockdown, but not HDAC2, increased c-Myc acetylation, suggesting selective roles in two enzymes. Chromatin immunoprecipitation assay revealed that HFD induced the binding of HDAC1 and deacetylated c-Myc at the Agt gene promoter. A putative c-Myc binding sequence in the promotor region was necessary for Agt transcription. Inhibition of c-Myc downregulated Agt and Ang II levels in kidney and serum, ameliorating HFD-induced hypertension. Thus, the abnormal HDAC1/2 in the kidney may be responsible for the upregulation of the Agt gene expression and hypertension. The results expose the pathologic HDAC1/c-myc signaling axis in kidney as a promising therapeutic target for obesity-associated resistant hypertension.
Topics: Animals; Male; Mice; Angiotensin II; Angiotensinogen; Diet, High-Fat; Hypertension; Mice, Inbred C57BL; Obesity; Proto-Oncogene Proteins c-myc; Signal Transduction
PubMed: 37244179
DOI: 10.1016/j.biopha.2023.114926 -
Pediatric Nephrology (Berlin, Germany) Nov 2023The current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of...
BACKGROUND
The current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of intrarenal renin-angiotensin system (RAS) status and the degree of infiltration of macrophages associated with RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.
METHODS
We measured baseline UAGT and UMCP-1 levels to examine the correlation between glomerular injury in 48 pediatric chronic glomerulonephritis patients before treatment. Furthermore, we performed immunohistochemical analysis of angiotensinogen (AGT) and CD68 in 27 pediatric chronic glomerulonephritis patients treated with RAS blockades and immunosuppressants for 2 years. Finally, we examined the effects of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells (MCs).
RESULTS
Baseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).
CONCLUSIONS
The data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.
Topics: Humans; Child; Renin-Angiotensin System; Angiotensinogen; Kidney; Chemokine CCL2; Glomerulonephritis; Angiotensin II; Chronic Disease; Immunosuppressive Agents; Macrophages
PubMed: 37231123
DOI: 10.1007/s00467-023-06026-5 -
Heliyon May 2023Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide... (Review)
Review
Angiotensin converting enzyme 2 (ACE2) is a homolog of ACE (a transmembrane bound dipeptidyl peptidase enzyme). ACE2 converts angiotensinogen to the heptapeptide angiotensin-(1-7). ACE2 and its product, angiotensin-(1-7), have counteracting effects against the adverse actions of other members of renin-angiotensin system (RAS). ACE2 and its principal product, angiotensin-(1-7), were considered an under recognized arm of the RAS. The COVID-19 pandemic brought to light this arm of RAS with special focus on ACE2. Membrane bound ACE2 serves as a receptor for SARS-CoV-2 viral entry through spike proteins. Apart from that, ACE2 is also involved in the pathogenesis of various other diseases like cardiovascular disease, cancer, respiratory diseases, neurodegenerative diseases and infertility. The present review focuses on the molecular mechanism of ACE2 in neurodegenerative diseases, cancer, cardiovascular disease, infertility and respiratory diseases, including SARS-CoV-2. This review summarizes unveiled roles of ACE2 in the pathogenesis of various diseases which further provides intriguing possibilities for the use of ACE2 activators and RAS modulating agents for various diseases.
PubMed: 37153428
DOI: 10.1016/j.heliyon.2023.e15644 -
Clinical and Experimental Nephrology Jul 2023Astragalus root is a commonly used herb in traditional Chinese medicine. Although renoprotective effects have been reported in some clinical and experimental studies,...
BACKGROUND
Astragalus root is a commonly used herb in traditional Chinese medicine. Although renoprotective effects have been reported in some clinical and experimental studies, the details remain unknown.
METHODS
We used 5/6 nephrectomized rats as chronic kidney disease (CKD) models. At 10 weeks, they were divided into four groups, namely, CKD, low-dose astragalus (AR400), high-dose astragalus (AR800), and sham groups. At 14 weeks, they were sacrificed for the evaluation of blood, urine, mRNA expression in the kidney, and renal histopathology.
RESULTS
Kidney dysfunction was significantly improved following astragalus administration (creatinine clearance: sham group; 3.8 ± 0.3 mL/min, CKD group; 1.5 ± 0.1 mL/min, AR400 group; 2.5 ± 0.3 mL/min, AR800 group; 2.7 ± 0.1 mL/min). Blood pressure, urinary albumin, and urinary NGAL levels were significantly lower in the astragalus-treated groups than those in the CKD group. Excretion of urinary 8-OHdG, an oxidative stress marker, and intrarenal oxidative stress were lower in the astragalus-treated groups than those in the CKD group. Furthermore, the mRNA expression of NADPH p22 phox, NADPH p47 phox, Nox4, renin, angiotensin II type 1 receptor, and angiotensinogen in the kidney was lower in the astragalus-treated groups compared with the CKD group.
CONCLUSION
This study suggests that astragalus root slowed CKD progression, possibly through the suppression of oxidative stress and the renin-angiotensin system.
Topics: Rats; Animals; NADP; Kidney; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; RNA, Messenger
PubMed: 37140734
DOI: 10.1007/s10157-023-02356-8 -
The Journal of Biological Chemistry Jun 2023Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2. The virus binds to angiotensinogen converting...
Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by severe acute respiratory syndrome coronavirus 2. The virus binds to angiotensinogen converting enzyme 2 (ACE2), which mediates viral entry into mammalian cells. COVID-19 is notably severe in the elderly and in those with underlying chronic conditions. The cause of selective severity is not well understood. Here we show cholesterol and the signaling lipid phosphatidyl-inositol 4,5 bisphosphate (PIP) regulate viral infectivity through the localization of ACE2's into nanoscopic (<200 nm) lipid clusters. Uptake of cholesterol into cell membranes (a condition common to chronic disease) causes ACE2 to move from PIP lipids to endocytic ganglioside (GM1) lipids, where the virus is optimally located for viral entry. In mice, age and high-fat diet increase lung tissue cholesterol by up to 40%. And in smokers with chronic disease, cholesterol is elevated 2-fold, a magnitude of change that dramatically increases infectivity of virus in cell culture. We conclude increasing the ACE2 location near endocytic lipids increases viral infectivity and may help explain the selective severity of COVID-19 in aged and diseased populations.
Topics: Animals; Mice; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Peptidyl-Dipeptidase A; Hypercholesterolemia; Cholesterol; Spike Glycoprotein, Coronavirus; Mammals
PubMed: 37119851
DOI: 10.1016/j.jbc.2023.104763