Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease

Abstract Background Angiotensin-converting enzyme 2 (ACE2) is a novel regulator of the renin–angiotensin system that counteracts the adverse effects of angiotensin II. In heart failure patients, elevated plasma ACE2 activity predicted adverse events and greater myocardial dysfunction. We aimed to describe plasma ACE2 activity and its clinical associations in patients with kidney disease. Methods Patients recruited from a single centre comprised of chronic kidney disease Stage III/IV (CKD), haemodialysis patients and kidney transplant recipients (KTRs). Plasma ACE2 enzyme activity was measured using a fluorescent substrate assay in plasma, collected at baseline and stored at −80°C. Linear regression was performed in both males and females separately to determine the covariates associated with log-transformed ACE2. Results The median (interquartile range) plasma ACE2 activity in pmol/mL/min was 15.9 (8.4–26.1) in CKD (n = 59), 9.2 (3.9–18.2) in haemodialysis (n = 100) and 13.1 (5.7–21.9) in KTR (n = 80; P < 0.01). In male haemodialysis patients, ACE2 activity was 12.1 (6.8–19.6) compared with 4.4 (2.5–10.3) in females (P < 0.01). Log-transformed ACE2 plasma activity was associated with post-haemodialysis systolic blood pressure in females [β-coefficient 0.04, 95% confidence interval (95% CI) 0.01–0.06, P = 0.006]. In males, log-transformed ACE2 plasma activity was associated with B-type natriuretic peptide (β-coefficient 0.39, 95% CI 0.19–0.60, P < 0.001). Plasma ACE2 activity was not associated with mortality. Conclusions Plasma ACE2 activity is reduced in haemodialysis patients compared with CKD patients, and in female haemodialysis patients compared with male. The different associations of plasma ACE2 activity between male and female haemodialysis patients indicate that the role of ACE2 in cardiovascular disease may differ by gender.

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Tissue-specific expression of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2, in mouse models of chronic kidney disease

Scientific Reports ◽

10.1038/s41598-021-96294-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shunichiro Tsukamoto ◽

Hiromichi Wakui ◽

Kengo Azushima ◽

Takahiro Yamaji ◽

Shingo Urate ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Angiotensin Converting Enzyme ◽

Functional Decline ◽

Converting Enzyme ◽

Specific Expression ◽

Tissue Specific ◽

Angiotensin Converting Enzyme 2 ◽

Tissue Specific Expression

AbstractElevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin–angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.

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Does Genetic Predisposition Contribute to the Exacerbation of COVID-19 Symptoms in Individuals with Comorbidities and Explain the Huge Mortality Disparity between the East and the West?

International Journal of Molecular Sciences ◽

10.3390/ijms22095000 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5000

Author(s):

Naoki Yamamoto ◽

Rain Yamamoto ◽

Yasuo Ariumi ◽

Masashi Mizokami ◽

Kunitada Shimotohno ◽

...

Keyword(s):

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Genetic Predisposition ◽

Genetic Factors ◽

The Elderly ◽

Converting Enzyme ◽

The West

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin–angiotensin–aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.

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