With the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) all over the world, there is an increasing number of children with such infection. Angiotensin-converting enzyme 2 (ACE2), one of the binding sites for SARS-CoV-2 infection in humans, can bind to viral spike proteins, allowing transmembrane serine protease (TMPRSS2) to activate S-protein to trigger infection and induce the production of various inflammatory factors such as interleukin-1, interferon-l, and tumor necrosis factor. Compared with adults, children tend to have lower expression levels of ACE2 and TMPRSS2, which are presumed to be associated with milder symptoms and fewer cases in children. The article summarizes the research advances in the role of ACE2 during SARS-CoV-2 infection, in order to help understand the pathogenic mechanism of SARS-CoV-2 and provide a reference for better development of drugs and vaccines to prevent and treat coronavirus disease 2019 in children.
Angiotensin-Converting Enzyme 2/metabolism* ; COVID-19 ; Child ; Humans ; Receptors, Virus/metabolism* ; SARS-CoV-2 ; Serine Endopeptidases/metabolism*

BACKGROUND/AIMS: Olmesartan, a widely used angiotensin II receptor blocker (ARB), has been linked to sprue-like enteropathy. No cases of olmesartan-associated enteropathy have been reported in Northeast Asia. We investigated the associations between olmesartan and other ARBs and the incidence of enteropathy in Korea. METHODS: Our retrospective cohort study used data from the Korean National Health Insurance Service to identify 108,559 patients (58,186 females) who were initiated on angiotensin converting enzyme inhibitors (ACEis), olmesartan, or other ARBs between January 2005 and December 2012. The incidences of enteropathy were compared among drug groups. Changes in body weight were compared after propensity score matching of patients in the ACEis and olmesartan groups. RESULTS: Among 108,559 patients, 31 patients were diagnosed with enteropathy. The incidences were 0.73, 0.24, and 0.37 per 1,000 persons, in the ACEis, olmesartan, and other ARBs groups, respectively. Adjusted rate ratios for enteropathy were: olmesartan, 0.33 (95% confidential interval [CI], 0.10 to 1.09; p = 0.070) and other ARBs, 0.34 (95% CI, 0.14 to 0.83; p = 0.017) compared to the ACEis group after adjustment for age, sex, income level, and various comorbidities. The post hoc analysis with matched cohorts revealed that the proportion of patients with significant weight loss did not differ between the ACEis and olmesartan groups. CONCLUSIONS: Olmesartan was not associated with intestinal malabsorption or significant body weight loss in the general Korean population. Additional large-scale prospective studies of the relationship between olmesartan and the incidence of enteropathy in the Asian population are needed.
Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Asia ; Asian Continental Ancestry Group ; Body Weight ; Cohort Studies* ; Comorbidity ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Incidence ; Insurance Claim Review ; Intestinal Diseases ; Korea ; National Health Programs ; Propensity Score ; Prospective Studies ; Receptors, Angiotensin ; Retrospective Studies ; Weight Loss

PURPOSE: Statins, metformin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been suggested for treating age-related macular degeneration (AMD) due to their pleiotropic effects. Therefore, we investigated whether these drugs prevent AMD. MATERIALS AND METHODS: We conducted a nested case-control study using the Korean National Health Insurance Service database. Using risk-set sampling of age, sex, cohort entry date, and follow-up duration, we identified incident patients with AMD and 10 matching controls in cohorts with diabetes mellitus or cardiovascular diseases. Exposure was assessed within one year before the index date using patient prescription records. We conducted conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between cardiovascular medications and AMD. RESULTS: Our study included 2330 cases and 23278 controls from a cohort of 231274 patients. The ORs (95% CI) for AMD occurrence in users prescribed with statins, metformin, ACE inhibitors, and ARBs were 1.12 (0.94–1.32), 1.15 (0.91–1.45), 0.90 (0.61–1.34), and 1.21 (1.05–1.39), respectively. A duration-response was not observed. CONCLUSION: Statins, metformin, ACE inhibitors, and ARBs did not inhibit AMD in elderly patients. The absence of a duration-response supports the lack of a causal relationship.
Aged ; Angiotensin II ; Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Cardiovascular Diseases ; Case-Control Studies ; Cohort Studies ; Diabetes Mellitus ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Logistic Models ; Macular Degeneration ; Metformin ; National Health Programs ; Odds Ratio ; Prescriptions ; Receptors, Angiotensin

Fimasartan, a new angiotensin II receptor antagonist, reduces myocyte damage and stabilizes atherosclerotic plaque through its anti-inflammatory effect in animal studies. We investigated the protective effects of pretreatment with fimasartan on ischemia-reperfusion injury (IRI) in a mouse model of ischemic renal damage. C57BL/6 mice were pretreated with or without 5 (IR-F5) or 10 (IR-F10) mg/kg/day fimasartan for 3 days. Renal ischemia was induced by clamping bilateral renal vascular pedicles for 30 min. Histology, pro-inflammatory cytokines, and apoptosis assays were evaluated 24 h after IRI. Compared to the untreated group, blood urea nitrogen and serum creatinine levels were significantly lower in the IR-F10 group. IR-F10 kidneys showed less tubular necrosis and interstitial fibrosis than untreated kidneys. The expression of F4/80, a macrophage infiltration marker, and tumor necrosis factor (TNF)-α, decreased in the IR-F10 group. High-dose fimasartan treatment attenuated the upregulation of TNF-α, interleukin (IL)-1β, and IL-6 in ischemic kidneys. Fewer TUNEL positive cells were observed in IR-F10 compared to control mice. Fimasartan caused a significant decrease in caspase-3 activity and the level of Bax, and increased the Bcl-2 level. Fimasartan preserved renal function and tubular architecture from IRI in a mouse ischemic renal injury model. Fimasartan also attenuated upregulation of inflammatory cytokines and decreased apoptosis of renal tubular cells. Our results suggest that fimasartan inhibited the process of tubular injury by preventing apoptosis induced by the inflammatory pathway.
Animals ; Apoptosis* ; Blood Urea Nitrogen ; Caspase 3 ; Constriction ; Creatinine ; Cytokines ; Fibrosis ; In Situ Nick-End Labeling ; Interleukin-6 ; Interleukins ; Ischemia ; Kidney ; Macrophages ; Mice ; Muscle Cells ; Necrosis ; Plaque, Atherosclerotic ; Receptors, Angiotensin ; Reperfusion Injury* ; Tumor Necrosis Factor-alpha ; Up-Regulation

To investigate changes in the angiotensin converting enzyme 2 (ACE2) and angiotensin (1-7) [Ang (1-7)] and to explore the role of ACE2-Ang (1-7)-Mas receptor axis in hypertension with heart failure with preserved ejection fraction (HFPEF).
 Methods: A total of 70 patients with primary hypertension and preserved left ventricular ejection fraction (LVEF>50%) were recruited and patients were divided into a hypertension group (HBP) and a heart failure with preserved ejection fraction group (HFpEF) according to the diagnostic criteria of HFpEF. Thirty-five healthy participants were selected randomly as a control group. Enzyme linked immunosorbent assays (ELISA) method was used to detect concentration of Ang (1-7), ACE2, angiotensin II (Ang II), brain natriuretic peptide (BNP) in plasma. Male Sprague- Dawley (SD) rats was randomly divided into 2 groups: An HFpEF group (n=16) and a sham group (n=8). Rats (n=8) in the AAC group were given Ang (1-7) [0.5 mg/(kg.d), intraperitoneally] for 6 weeks, and the rest were given equal dose normal saline. Then all the rats were killed, and the hearts were taken out for hematoxylineosin (HE) staining. The protein expressions of angiotensin converting enzyme (ACE), ACE2, and Mas receptor were detected by Western blot.
 Results: The BNP and Ang II were significantly increased in the HBP group and the HFpEF group compared with the control group (P<0.01). There were not significantly different in levels of ACE2 and Ang (1-7) between the HBP group and control group (P>0.05), whereas those levels were significantly increased in the HFpEF group compared with the HBP group and control group (P<0.01). HE staining showed obvious hypertrophy of myocardial cell in the AAC group compared with the sham group. Hypertrophy of myocardial cell in the AAC+Ang (1-7) group was significantly higher than that in the AAC group. Expressions of ACE, ACE2, and Mas receptor proteins were significantly higher in the AAC group than those in the sham group (P<0.05), while the expressions of ACE2 and Mas receptor proteins in the AAC+Ang (1-7) group were significantly higher than those in the AAC group (P<0.05). There was no significant difference in the ACE protein expression between groups (P>0.05).
 Conclusion: ACE2 and Ang (1-7) are important predictive factors for the severity of heart failure and myocardial remodeling of HFpEF with hypertension; ACE2-Ang (1-7)-Mas receptor axis may play a protective role in preventing myocardial remodeling in HFpEF with hypertension.
Angiotensin I ; physiology ; Angiotensin II ; Animals ; Atrial Remodeling ; physiology ; Case-Control Studies ; Enzyme-Linked Immunosorbent Assay ; Heart Failure ; metabolism ; physiopathology ; Humans ; Hypertension ; metabolism ; physiopathology ; Male ; Peptide Fragments ; physiology ; Peptidyl-Dipeptidase A ; physiology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, G-Protein-Coupled ; physiology ; Stroke Volume ; Ventricular Function, Left ; physiology ; Ventricular Remodeling ; physiology

BACKGROUND: Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD). We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs) and its potential mechanisms in hypertensive CKD patients. METHODS: This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. RESULTS: Fifty-eight participants (25.6%) were assigned to group 1 (≥1.5% decrease in body weight after 16 weeks), 32 participants (14.1%) were assigned to group 2 (1.5–0.1% decrease in body weight), and 136 participants (59.9%) were assigned to group 3 (≥ 0.0% increase in body weight). Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017). Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913–20.315, P = 0.002). Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013). CONCLUSION: We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage.
Albuminuria ; Angiotensin II* ; Angiotensin Receptor Antagonists* ; Angiotensins* ; Body Weight ; Cytokines ; Humans ; Hypertension ; Life Style ; Podocytes ; Proteinuria* ; Receptors, Angiotensin* ; Renal Insufficiency, Chronic* ; Sodium ; Weight Loss*

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1–7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1–7)/Mas receptor and ACE2/Ang-(1–9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.
Angiotensin-Converting Enzyme Inhibitors ; Angiotensins ; Cell Proliferation ; Fibrosis* ; Hemodynamics ; Humans ; Hypertension, Portal* ; Inflammation ; Liver Cirrhosis ; Mineralocorticoid Receptor Antagonists ; Receptors, Angiotensin ; Renin-Angiotensin System* ; Sodium ; Vasoconstriction ; Vasodilation

An overdose of antihypertensive agents, such calcium channel blockers (CCBs) and angiotensin II receptor blocker (ARBs), and the antihyperglycemic agent, metformin, leads to hypotension and lactic acidosis, respectively. A 40-year-old hypertensive and diabetic man with hyperlipidemia and a weight of 110 kg presented to the emergency room with vomiting, dizziness, and hypotension following an attempted drug overdose suicide with combined CCBs, ARBs, 3-hydroxy-3-methylglutaryl-coemzyme A reductase inhibitors, and metformins. A conventional medical treatment initially administered proved ineffective. The treatment was then changed to simultaneous extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), which was effective. This shows that simultaneous ECMO and CRRT can be an effective treatment protocol in cases of ineffective conventional medical therapy for hypotension and lactic acidosis due to an overdose of antihypertensive agents and metformin, respectively.
Acidosis, Lactic ; Adult ; Antihypertensive Agents ; Calcium Channel Blockers* ; Calcium Channels* ; Calcium* ; Clinical Protocols ; Dizziness ; Drug Overdose ; Emergency Service, Hospital ; Extracorporeal Membrane Oxygenation* ; Humans ; Hyperlipidemias ; Hypotension ; Metformin* ; Oxidoreductases ; Receptors, Angiotensin ; Renal Replacement Therapy* ; Suicide ; Vomiting

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared the pharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) and healthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease of blood pressure (BP) was not clinically significant in those with moderate hepatic impairment. The aims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartan and to evaluate the effect of hepatic function on BP reduction by fimasartan using previously published data. A 2-compartment linear model with mixed zero-order absorption followed by first-order absorption with a lag time adequately described fimasartan PK, and the effect of fimasartan on BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD model overlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model, the lower BP responses in hepatic impairment were the result of the increased fimasartan EC₅₀ in patients, rather than from a saturation of effect. This is congruent with the reported pathophysiological change of increased plasma ACE and renin activity in hepatic cirrhosis.
Absorption ; Blood Pressure ; Circadian Rhythm ; Colon, Sigmoid ; Healthy Volunteers ; Humans ; Linear Models ; Liver Cirrhosis* ; Liver* ; Pharmacokinetics ; Plasma ; Receptors, Angiotensin ; Renin

Indoxyl sulfate, a protein-bound uremic toxin, leads to CKD (chronic kidney disease) progression and its complications through the activation of AhR (aryl hydrocarbon receptor) and RAS (renin-angiotensin system). Inhibition of these pathways may slow the development of CKD and CKD-associated complications.
Indican ; Kidney ; Receptors, Aryl Hydrocarbon* ; Renal Insufficiency, Chronic ; Renin-Angiotensin System*