Kidney and Lung ACE2 Expression after an ACE Inhibitor or an Ang II Receptor Blocker: Implications for COVID-19.
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ABSTRACT:
SUBMITTER: Wysocki J
PROVIDER: S-EPMC7461678 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Potential but unconfirmed risk factors for coronavirus disease 2019 (COVID-19) in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, ACE (angiotensin-converting enzyme) inhibitors, and Ang II (angiotensin II) receptor blockers. Coronavirus binding to ACE2 (angiotensin-converting enzyme 2), a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus, but the reasons are unclear. This review will highlight the relationship of COVID-19 with hypertension, use of ACE inhibitors and Ang II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the ACE 2/Ang-(1-7) pathway in children and the clinical evidence for how ACE inhibitors and Ang II receptor blockers affect this important pathway. Given the importance of the ACE 2/Ang-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe COVID-19.
| S-EPMC7289676 | biostudies-literature
Project description:Hypertension (HTN) is the most common chronic disease in the USA. Hypertensive patients frequently require repeat primary care visits to find an effective drug or drug combination to control their disease. Currently, patients are prescribed drugs for HTN based on race, age, and comorbidities and although the current guidelines are reasonable starting points for prescribing, 50% of hypertensive patients still fail to achieve target blood pressures. Despite numerous strategies to improve compliance, drug effectiveness, and optimization of initial drug choice, effectiveness has remained largely unchanged over the past two decades. Therefore, it is important to pursue alternative strategies to more effectively treat patients and to decrease medical costs. Additional precision medicine work is needed to identify factors associated with effectiveness of commonly used antihypertensive medications. The objective of this manuscript is to present a comprehensive review of the pharmacogenomic and metabolomic factors associated with ACEI and ARB effectiveness and safety.
| S-EPMC5727913 | biostudies-literature
Project description:Background:Angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (ACE-I/ARB) improve outcomes in patients with heart failure and reduced left-ventricular (LV) systolic function. However, these medications can cause a rise in serum creatinine and their benefits in patients with HF accompanied by kidney disease are less certain. Objective:To characterize associations between estimated glomerular filtration rate (eGFR), patterns of ACE-Is and ARBs use, and 1-year survival following hospitalization for heart failure (HF). Design:We formed a retrospective cohort study of patients admitted with HF and followed HF medication prescriptions using the pharmaceutical information network, stratified by discharge eGFR. Setting:Cardiology services in 3 centers in Southern Alberta, Canada. Patients:The study cohort included patients admitted to hospital with a clinical diagnosis of HF. Measurements:eGFR was determined from inpatient laboratory data prior to discharge. Outpatient prescription data prior to and following the index hospitalization was obtained using the Pharmaceutical Information Network of Alberta and survival was determined from provincial vital statistics. Methods:Characteristics of the HF cohort were obtained from the Admissions Module of the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database. Multivariable Cox proportional hazards models were used to evaluate the association between time-varying ACE-I/ARB use, and mortality, and to test whether eGFR modified this association. Results:Totally, 1404 patients were included. Within the first 3 months following discharge, ACE-I/ARBs were used in 71%, 67%, 62%, and 52% for those with eGFR > 90, 45-89, 30-44, and < 30 mL/min/1.73 m2, respectively, with differences in use persisting after 1 year of follow-up. Patients with eGFR < 45 mL/min/1.73 m2 had significantly lower rates of ACE-I/ARB use following hospitalization. In adjusted models, ACE-I/ARB use following discharge was associated with 25% lower risk of mortality (Hazard Ratio [HR]: 0.75, 95% confidence interval [CI]: 0.61-0.92; P < 0.01), without evidence that this association differed by eGFR (P = 0.75). Limitations:LV function measurements were not available for the cohort. Due to the observation design of the study, treatment-selection bias may be present. Conclusion:Patients with HF and reduced eGFR at time of hospital discharge were less likely to receive ACE-I/ARB despite these medications being associated with lower mortality independent of eGFR. These findings demonstrate the need for further research on strategies for safe use of ACE-I and ARB in patients with HF and kidney disease.
| S-EPMC6194922 | biostudies-literature
Project description:BACKGROUND AND AIMS:Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD. METHODS AND RESULTS:HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA. CONCLUSION:Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.
| S-EPMC5959764 | biostudies-literature
Project description:This study aimed to evaluate AT1-R expression in normal and cancerous human kidneys, how these expressions are modified, and AT1-R functionality. AT-1R mRNA expression, determined by real-time PCR, was detected in all samples. AT-1R mRNA increased in well-differentiated cancer (G1, p < 0.01) and decreased 2.9-fold in undifferentiated cancer (G4, p < 0.001) compared with normal kidney tissues. Immunocytochemistry analysis showed that the AT-1R was expressed in the normal tubular epithelium. The glomerulus was also immunoreactive, and as expected, the smooth muscle cells of the vessel walls also expressed the receptor. A total of 35 out of 42 tumors were AT-1R positive, with the cell tumors showing varying numbers of immunoreactive cells, which were stained in a diffuse cytoplasmic and membranous pattern. Computer-assisted counting of the stained tumor cells showed that the number of AT-1R-positive cells increased in the well-differentiated cancers. The functionality of AT-1R was assessed in primary cultures of kidney epithelial cells obtained from three G3 kidney cancer tissues and corresponding histologically proven non-malignant tissue adjacent to the tumor. Indeed, Ang II stimulated, in a dose-dependent manner, the 24 h proliferation of normal kidney cells and cancer cells in the primary culture and phosphorylated extracellular regulated kinases 1 and 2. In conclusion, Ang II may be involved in the growth or function of neoplastic kidney tissue.
| S-EPMC10452411 | biostudies-literature
Project description:BackgroundACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing.Methods and findingsEnglish NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p<0.001) that increases in practice-level prescribing of ACE-I/ARA over the study period were associated with an increase in AKI admission rates. The increase in prescribing seen in a typical practice corresponded to an increase in admissions of approximately 5.1% (rate ratio?=?1.051 for a 0.03 per ASTRO-PU increase in annual prescribing rate, 95%CI 1.047-1.055). Using the regression model we predict that 1,636 (95%CI 1,540-1,780) AKI admissions would have been avoided if prescribing rates were at the 2007/8 level, equivalent to 14.8% of the total increase in AKI admissions.ConclusionIn this ecological analysis, up to 15% of the increase in AKI admissions in England over a 4-year time period is potentially attributable to increased prescribing of ACE-I and ARAs. However, these findings are limited by the lack of patient level data such as indication for prescribing and patient characteristics.
| S-EPMC3819379 | biostudies-literature
Project description:Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of chronic kidney disease (CKD) and is a membrane receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease (COVID-19), whereas transmembrane protease, serine 2 (TMPRSS2) is involved in viral attachment. Together, tissue expression of ACE2 and TMPRSS2 may determine infection. Sex, age, body mass index (BMI), and CKD are clinical risk factors for COVID-19 severity, but the relationships between kidney ACE2 and TMPRSS2 expression and these clinical variables are unknown. Accordingly, we obtained renal tubulointerstitial and glomerular microarray expression data and clinical variables from healthy living donors (HLD) and patients with CKD from the European Renal cDNA Bank. ACE2 expression was similar in the tubulointerstitium of the two groups, but greater in females than males in HLD (P = 0.005) and CKD (P < 0.0001). ACE2 expression was lower in glomeruli of CKD patients compared to HLD (P = 0.0002) and lower in males than females. TMPRSS2 expression was similar in the tubulointerstitium but lower in glomeruli of CKD patients compared to HLD (P < 0.0001). There was a strong relationship between ACE2 and TMPRSS2 expression in the glomerulus (r = 0.51, P < 0.0001). In CKD, there was a relationship between tubulointerstitial ACE2 expression and estimated glomerular filtration rate (r = 0.36, P < 0.0001) and age (r = -0.17, P = 0.03), but no relationship with BMI. There were no relationships between TMPRSS2 expression and clinical variables. Genes involved in inflammation (CCL2, IL6, and TNF) and fibrosis (COL1A1, TGFB1, and FN1) were inversely correlated with ACE2 expression. In summary, kidney expression of ACE2 and TMPRSS2 differs in HLD and CKD. ACE2 is related to sex and eGFR. ACE2 is also associated with expression of genes implicated in inflammation and fibrosis.
| S-EPMC7598523 | biostudies-literature
Project description:Angioedema occurring in the head and neck region is a rare and sometimes life-threatening adverse reaction to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI-induced angioedema (ACEI-AE) or ARB-induced angioedema (ARB-AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI-AE, ARB-AE, and 658 controls) was performed using exome-enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI-AE and ARB-AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89-4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI-AE or ARB-AE, P = 2.09 × 10-3 . A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49-3.27, P = 6.30 × 10-9 ) times the odds of having ACEI-AE or ARB-AE. The increased risk due to the common Leiden allele was confirmed in a genome-wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect-causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI-AE or ARB-AE.
| S-EPMC10306231 | biostudies-literature
Project description:BackgroundAlthough hypertension is common in CKD and evidence-based treatment of hypertension has changed considerably, contemporary and nationally representative information about use of angiotensin-converting enzyme (ACEs) inhibitors or angiotensin II receptor blockers (ARBs) in CKD is lacking.MethodsWe examined ACE/ARB trends from 1999 to 2014 among 38,885 adult National Health and Nutrition Examination Survey participants with creatinine-based eGFR<60 ml/min per 1.73 m2 or urinary albumin-to-creatinine ratio ≥30 mg/g.ResultsOf 7085 participants with CKD, 34.9% used an ACE/ARB. Across four eras studied, rates of use rose significantly (rates were 25.5% in 1999-2002, 33.3% in 2003-2006, 39.0% in 2007-2010, and 40.1% in 2011-2014) but appeared to plateau after 2003. Among those with CKD, use was significantly greater among non-Hispanic white and black individuals (36.1% and 38.2%, respectively) and lower among Hispanic individuals (26.7%) and other races/ethnicities (29.3%). In age-, sex-, and race/ethnicity-adjusted models, ACE/ARB use was significantly associated with era (adjusted odds ratios [aOR], 1.41; 95% confidence interval [95% CI], 1.14 to 1.74 for 2003-2006, 1.84; 95% CI, 1.48 to 2.28 for 2007-2010, and 2.02; 95% CI, 1.61 to 2.53 for 2011-2014 versus 1999-2002); it also was significantly associated with non-Hispanic black versus non-Hispanic white race/ethnicity (aOR, 1.40; 95% CI, 1.19 to 1.66). Other multivariate associations included older age, men, elevated BMI, diabetes mellitus, treated hypertension, cardiac failure, myocardial infarction, health insurance, and receiving medical care within the prior year.ConclusionsRates of ACE/ARB use increased in the early 2000s among United States adults with CKD, but for unclear reasons, use appeared to plateau in the ensuing decade. Research examining barriers to care and other factors is needed.
| S-EPMC6622408 | biostudies-literature
Project description:The angiotensin-converting enzyme (ACE)/Angiotensin II (Ang II) and angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) (Ang-(1-7)) pathways are coexpressed in most tissues. The balance between these pathways determines, at least in part, whether tissue damage will occur in response to pathological stimuli. The present study tested the hypothesis that male sex and high blood pressure are associated with ACE/ACE2 imbalance in the lungs. Experiments were conducted in male and female Wistar rats and spontaneously hypertensive rats (SHRs). Lung ACE and ACE2 gene expression was also evaluated in normotensive and hypertensive humans using the Genotype-Tissue Expression (GTEx) project. Compared with Wistar rats and female SHRs, male SHRs displayed reduced lung ACE2 mRNA, ACE2 protein abundance and ACE2 activity, and increased Ang II concentration. Lung ACE mRNA levels were higher in male SHRs than in Wistar rats, whereas lung ACE protein abundance and activity were similar among the four groups of rats. Lung Ang-(1-7) concentration was higher in female than in male SHRs (89 ± 17 vs. 43 ± 2 pg/g, P<0.05). Lung ACE to ACE2 mRNA expression in hypertensive patients was significantly higher than that in normotensive subjects. Taken together, these results demonstrate that male hypertensive rats display imbalance between the ACE/Ang II and ACE2/Ang-(1-7) pathways in the lungs mainly attributable to ACE2 down-regulation. Further studies should be conducted to investigate whether this imbalance between ACE/ACE2 may promote and accelerate lung injury in respiratory infections, including coronavirus disease 2019 (COVID-19).
| S-EPMC8655502 | biostudies-literature