Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney.
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ABSTRACT: Aims
Angiotensin-converting enzyme 2 (ACE2) is the cellular entry point for severe acute respiratory syndrome coronavirus (SARS-CoV-2)-the cause of coronavirus disease 2019 (COVID-19). However, the effect of renin-angiotensin system (RAS)-inhibition on ACE2 expression in human tissues of key relevance to blood pressure regulation and COVID-19 infection has not previously been reported.Methods and results
We examined how hypertension, its major metabolic co-phenotypes, and antihypertensive medications relate to ACE2 renal expression using information from up to 436 patients whose kidney transcriptomes were characterized by RNA-sequencing. We further validated some of the key observations in other human tissues and/or a controlled experimental model. Our data reveal increasing expression of ACE2 with age in both human lungs and the kidney. We show no association between renal expression of ACE2 and either hypertension or common types of RAS inhibiting drugs. We demonstrate that renal abundance of ACE2 is positively associated with a biochemical index of kidney function and show a strong enrichment for genes responsible for kidney health and disease in ACE2 co-expression analysis.Conclusion
Our results indicate that neither hypertension nor antihypertensive treatment is likely to alter the expression of the key entry receptor for SARS-CoV-2 in the human kidney. Our data further suggest that in the absence of SARS-CoV-2 infection, kidney ACE2 is most likely nephro-protective but the age-related increase in its expression within lungs and kidneys may be relevant to the risk of SARS-CoV-2 infection.
SUBMITTER: Jiang X
PROVIDER: S-EPMC7665509 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), commonly used antihypertensive drugs, may have a protective effect against depression in older individuals, but evidence in humans is limited.AimsWe evaluated the risk of depression, among older individuals with hypertension, comparing ACE or ARB initiators to thiazide(-like) diuretic initiators. Thiazide(-like) diuretics were used as control because these drugs are not associated with mood disorders.MethodsWe used a propensity score-matched new user cohort design with routinely collected data from general practices in England from the Clinical Practice Research Datalink database. We matched 12,938 pairs of new users of ACEIs/ARBs and thiazide(-like) diuretics with hypertension (mean age 67.6 years; 54.7% women). Follow-up time started on the date of drug initiation and ended on the date of treatment discontinuation plus 30 days, or switch to a comparator, occurrence of a study event, death, date of patient's transfer out of practice, or end of the study period. The primary outcome was a composite endpoint of treated depression and nonfatal and fatal self-harm.Results/outcomesCompared to the thiazide(-like) diuretic group, ACEIs/ARBs use was not associated with a lower risk of the primary outcome (hazard ratio 0.96 (95% confidence interval: 0.79; 1.15)). Results did not differ according to lipophilicity, duration of use, and average daily dose, or class (ACEIs or ARBs).Conclusions/interpretationNew use of ACEIs or ARBs is not associated with a lower risk of depression among individuals with hypertension.
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Project description:Rationale: Smoking is a major risk factor for the development of cardiovascular and pulmonary diseases. The importance of the renin–angiotensin system in the development of cardiovascular and pulmonary disease is well established. Angiotensin-II, by means of its type 1 receptor (angiotensin type 1 receptor, AT1R), promotes increased sympathetic activity, salt and water reabsorption, vasoconstriction, inflammation, and aldosterone and vasopressin release, contributing to tissue fibrosis, endothelium dysfunction, and hypertension. Angiotensin-converting enzyme 2 cleaves angiotensin-II into the vasodilator peptide, angiotensin-(1–7), hence playing a pivotal role in the angiotensin-converting enzyme 2/angiotensin-(1–7) compensatory axis of the renin–angiotensin system. Angiotensin type 2 receptor (AT2R), another receptor for angiotensin-II, opposes the deleterious effects of AT1R activation, and angiotensin-converting enzyme 2–formed angiotensin-(1–7) has been shown to activate AT2R. Objectives: The goal of the present study was to examine how nicotine, the addictive component of cigarette smoke, alters the homeostasis of the renin–angiotensin system. Methods: Quantitative real-time polymerase chain reaction was performed to examine the expression of the components of the renin–angiotensin system after cigarette smoke exposure or direct nicotine inhalation. Radio telemetry was used for continuous blood pressure recording in conscious, unrestrained mice. Results: Our study showed that cigarette smoke or direct nicotine inhalation inhibits the expression of angiotensin-converting enzyme 2/AT2R in multiple organs and cell types. In the lung, cigarette smoke (6 cigarettes/d, 12 wk) inhibited the expression of both angiotensin-converting enzyme 2 and AT2R. In cardiac fibroblasts, nicotine exposure resulted in near complete suppression of angiotensin-converting enzyme 2 and AT2R. In the brain, nicotine vapor inhalation inhibited angiotensin-converting enzyme 2 expression in the hypothalamus, a region involved in central regulation of cardiopulmonary function. In addition, cultured Neuro2A cells exposed to nicotine showed a dose-dependent reduction of enzymatic activity of angiotensin-converting enzyme 2. Functionally, mice exposed to nicotine vapor (12 h/d, 4 wk) exhibited significantly increased mean arterial blood pressure, which was more pronounced during the night active cycle (mean?±?SE, 124?±?0.6 mm Hg in nicotine vapor–exposed mice vs. 107?±?0.4 mm Hg in air control mice; P <?0.0001). Conclusions: Our findings suggest that, by downregulating the compensatory angiotensin-converting enzyme 2/AT2R elements, nicotine disrupts the homeostasis of the renin–angiotensin system in multiple organs, which is likely an important mechanism leading to the development of cardiovascular and pulmonary disease.
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