In times of coronavirus disease 2019 (COVID-19), the impact of severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 infection on pregnancy is still unclear. The presence of angiotensin-converting enzyme (ACE) 2 (ACE2), the main receptor for SARS-CoV-2, in human placentas indicates that this organ can be vulnerable for viral infection during pregnancy. However, for this to happen, additional molecular processes are critical to allow viral entry in cells, its replication and disease manifestation, particularly in the placenta and/or feto–maternal circulation. Beyond the risk of vertical transmission, COVID-19 is also proposed to deplete ACE2 protein and its biological actions in the placenta. It is postulated that such effects may impair essential processes during placentation and maternal hemodynamic adaptations in COVID-19 pregnancy, features also observed in several disorders of pregnancy. This review gathers information indicating risks and protective features related to ACE2 changes in COVID-19 pregnancies. First, we describe the mechanisms of SARS-CoV-2 infection having ACE2 as a main entry door and current evidence of viral infection in the placenta. Further, we discuss the central role of ACE2 in physiological systems such as the renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS), both active during placentation and hemodynamic adaptations of pregnancy. Significant knowledge gaps are also identified and should be urgently filled to better understand the fate of ACE2 in COVID-19 pregnancies and the potential associated risks. Emerging knowledge will be able to improve the early stratification of high-risk pregnancies with COVID-19 exposure as well as to guide better management and follow-up of these mothers and their children.
Coronavirus disease 2019 (COVID-19) was first reported in late December 2019 in Wuhan, China. The etiological agent of this disease is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the high transmissibility of the virus led to its rapid global spread and a major pandemic (ongoing at the time of writing this review). The clinical manifestations of COVID-19 can vary widely from non-evident or minor symptoms to severe acute respiratory syndrome and multi-organ damage, causing death. Acute kidney injury (AKI) has been recognized as a common complication of COVID-19 and in many cases, kidney replacement therapy (KRT) is required. The presence of kidney abnormalities on hospital admission and the development of AKI are related to a more severe presentation of COVID-19 with higher mortality rate. The high transmissibility and the broad spectrum of clinical manifestations of COVID-19 are in part due to the high affinity of SARS-CoV-2 for its receptor, angiotensin (Ang)-converting enzyme 2 (ACE2), which is widely expressed in human organs and is especially abundant in the kidneys. A debate on the role of ACE2 in the infectivity and pathogenesis of COVID-19 has emerged: Does the high expression of ACE2 promotes higher infectivity and more severe clinical manifestations or does the interaction of SARS-CoV-2 with ACE2 reduce the bioavailability of the enzyme, depleting its biological activity, which is closely related to two important physiological systems, the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS), thereby further contributing to pathogenesis. In this review, we discuss the dual role of ACE2 in the infectivity and pathogenesis of COVID-19, highlighting the effects of COVID-19-induced ACE2 depletion in the renal physiology and how it may lead to kidney injury. The ACE2 downstream regulation of KKS, that usually receives less attention, is discussed. Also, a detailed discussion on how the triad of symptoms (respiratory, inflammatory, and coagulation symptoms) of COVID-19 can indirectly promote renal injury is primary aborded.
Coronavirus disease 2019 (COVID-19) is a rapid-spread infectious disease caused by the SARS-CoV-2 virus, which can culminate in the renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) systems imbalance, and in serious consequences for infected patients. This scoping review of published research exploring the RAAS and KKS was undertaken in order to trace the history of the discovery of both systems and their multiple interactions, discuss some aspects of the viral-cell interaction, including inflammation and the system imbalance triggered by SARS-CoV-2 infection, and their consequent disorders. Furthermore, we correlate the effects of continued use of the RAAS blockers in chronic diseases therapies with the virulence and physiopathology of COVID-19. We also approach the RAAS and KKS-related proposed potential therapies for treatment of COVID-19. In this way, we reinforce the importance of exploring both systems and the application of their components or their blockers in the treatment of coronavirus disease.
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Angiotensin converting enzyme (ACE) upregulation in adults contributes to cardiometabolic diseases including dyslipidemia and atherosclerosis. Objective: Investigate whether ACE activity is modulated in pediatric dyslipidemia. Methods: We evaluated anthropometric measurements, blood pressure and fasting lipid concentrations of 360 individuals (190 boys and 170 girls) aged from 6 to 19 year (mean 11.6). Categorization was done according to the levels of each lipoprotein (Total cholesterol (TC), triglycerides (TG), LDL-C, HDL-C, and non-HDL) into three groups: normolipidemic, borderline and dyslipidemic; reference values were according to American Academy of Pediatrics and Brazilian Pediatric Society. ACE activity in urine was measured with the substrates Z-FHL-OH and hippuryl-HL-OH. ACE activity ratio to infer N-domain activity was calculated (Z-FHL/h-HL). Results: Dyslipidemic levels of HDL-C, TG and LDL-C were observed in 23%, 9% and 3% of the participants, respectively. These clinical alterations were more frequent in obese children (Chi-square, p <0.001). ACE activity (Z-FHL) was higher in the groups with borderline and dyslipidemic values of HDL-C than in normolipidemic group (0.077 vs 0.070 vs 0.037 nmol/min/mg of creatinine, p = 0.01). The ratio of ACE activity was augmented in HDL-C borderline group when compared to HDL-C normolipidemic group (5.06 vs 2.39, p <0.01) and in LDL-C dyslipidemic group than in LDL-C borderline and LDL-C normolipidemic groups (8.66 vs 1.84 vs 2.88, p = 0.02). Volunteers with normal levels of TG presented lower diastolic blood pressure (DBP) mmHg (p = 0.02), percentile of DBP (p < 0.01), and percentile of systolic blood pressure (SBP) (p <0.01) than volunteers with borderline and dyslipidemic levels of TG. Also, increased DBP mmHg was observed in borderline and dyslipidemic HDL-C groups when compared to normolipidic HDL-C group. Conclusion: Pediatric hypertriglyceridemia, HDL-C deficiency and high LDL-C were related to higher urinary ACE activity (mainly N-domain). ACE modulation can contribute to higher risk of hypertension and other cardiometabolic alterations still in childhood and adolescence. Also, impairment in lipoprotein levels was associated with higher blood pressure values.
Impairment in metabolic pathways is associated with cardiometabolic diseases such as obesity, diabetes and cardiovascular diseases. Obesity, for instance, is a multifactorial disease that is linked to physical, social, psychological and economic burdens being characterized as a health public problem. Childhood obesity is tightly related with obesity and cardiovascular problems in adulthood. Inadequate diet and lifestyle in early childhood can contribute to alterations in the metabolites levels and development of childhood obesity and associated diseases. In this cross‐sectional study it was evaluated the profile of amino acids in urine of 110 children that were classified in into three groups of nutritional status according to their BMI (Body Mass Index), as normal weight (NW) (n=46), overweight (OW) (n=22) and obese (OB) (n=45). The 24 hours urine samples were submitted to LC–MS/MS for evaluation of 47 amino acids using the Amino Acids Analysis Kit (Zivak®, Turkey), values were corrected by creatinine concentration. Biochemical profile, cardiovascular parameters and anthropometric measurements were assessed following standard protocols. The following amino acids were found in higher concentrations in urine of children with overweight or obesity, when compared with normal weight group, glutamine (NW: 1024.3 vs OW: 1309.2 nmol/mg of creatinine, p=0.05), tryptophan (NW: 85.65, OW:113.55, OB:109.36 nmol/mg of creatinine; NW vs OW p=0.01; OW vs OB p=0.004), phenylalanine (NW: 43.04, OW:49.66, OB:72.08 nmol/mg of creatinine; NW vs OB p=0.01; OW vs OB p=0.04), Tyrosine (NW: 85.07, OW: 109.74, OB: 140.54 nmol/mg of creatinine; NW vs OB p<0.01; OW vs OB p=0.04).In addition, sarcosine showed reduced concentrations for obese participants (OW: 78.7 vs OB: 62.3, p=0.04). The urine levels of glutamine and of the aromatic amino acids were influenced by nutritional status being higher in OW and OB children. Interestingly, the tryptophan showed a positive correlation with the BMI of the participant's mother. Also, tryptophan andtyrosine were negatively correlated with HDL, while phenylalanine and tyrosine hada positive correlation with triglycerides levels. Tyrosine also showed a positive association with systolic blood pressure values. In our results, the correlation between the concentrations of the aromatic amino acids and the increase in children's obesity levels stands out, and this corroborates with the literature data and can represent markers of obesity.
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