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ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

ABSTRACT: The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

SUBMITTER: Lee IT

PROVIDER: S-EPMC7595232 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

Lee Ivan T IT Nakayama Tsuguhisa T Wu Chien-Ting CT Goltsev Yury Y Jiang Sizun S Gall Phillip A PA Liao Chun-Kang CK Shih Liang-Chun LC Schürch Christian M CM McIlwain David R DR Chu Pauline P Borchard Nicole A NA Zarabanda David D Dholakia Sachi S SS Yang Angela A Kim Dayoung D Chen Han H Kanie Tomoharu T Lin Chia-Der CD Tsai Ming-Hsui MH Phillips Katie M KM Kim Raymond R Overdevest Jonathan B JB Tyler Matthew A MA Yan Carol H CH Lin Chih-Feng CF Lin Yi-Tsen YT Bau Da-Tian DT Tsay Gregory J GJ Patel Zara M ZM Tsou Yung-An YA Tzankov Alexandar A Matter Matthias S MS Tai Chih-Jaan CJ Yeh Te-Huei TH Hwang Peter H PH Nolan Garry P GP Nayak Jayakar V JV Jackson Peter K PK

Nature communications 20201028 1

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 r ...[more]

PMID: 33116139

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Project description:A 2007 systematic review compared angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in patients with hypertension. Direct renin inhibitors (DRIs) have since been introduced, and significant new research has been published. We sought to update and expand the 2007 review.We searched MEDLINE and EMBASE (through December 2010) and selected other sources for relevant English-language trials.We included studies that directly compared ACE inhibitors, ARBs, and/or DRIs in at least 20 total adults with essential hypertension; had at least 12 weeks of follow-up; and reported at least one outcome of interest. Ninety-seven (97) studies (36 new since 2007) directly comparing ACE inhibitors versus ARBs and three studies directly comparing DRIs to ACE inhibitor inhibitors or ARBs were included.A standard protocol was used to extract data on study design, interventions, population characteristics, and outcomes; evaluate study quality; and summarize the evidence.In spite of substantial new evidence, none of the conclusions from the 2007 review changed. The level of evidence remains high for equivalence between ACE inhibitors and ARBs for blood pressure lowering and use as single antihypertensive agents, as well as for superiority of ARBs for short-term adverse events (primarily cough). However, the new evidence was insufficient on long-term cardiovascular outcomes, quality of life, progression of renal disease, medication adherence or persistence, rates of angioedema, and differences in key patient subgroups.Included studies were limited by follow-up duration, protocol heterogeneity, and infrequent reporting on patient subgroups.Evidence does not support a meaningful difference between ACE inhibitors and ARBs for any outcome except medication side effects. Few, if any, of the questions that were not answered in the 2007 report have been addressed by the 36 new studies. Future research in this area should consider areas of uncertainty and be prioritized accordingly.

Project description:BackgroundReducing patient cost-sharing and engaging patients in disease management activities have been shown to increase uptake of evidence-based care.ObjectiveTo evaluate the effect of employer purchase of a disease-specific plan with reduced cost-sharing and disease management (the Diabetes Health Plan/DHP) on medication adherence among eligible employees and dependents.DesignEmployer-level "intent to treat" cohort study, including data from eligible employees and their dependents with diabetes, regardless of whether they were enrolled in the DHP.SettingEmployers that contracted with a large national health plan administrator in 2009, 2010, and/or 2011.ParticipantsTen employers that purchased the DHP and 191 employers that did not (controls). Inverse probability weighting (IPW) estimation was used to adjust for inter-group differences.InterventionThe DHP includes free or low-cost medications and physician visits. Enrollment strategies and specific benefit designs are determined by the employer and vary in practice. DHP participants are notified up front that they must engage in their own health care (e.g., receiving diabetes-related screening) in order to remain enrolled.Main outcome measureMean employee adherence to metformin, statins, and ACE/ARBs at the employer level at one year post-DHP implementation, as measured by the proportion of days covered (PDC).ResultsBaseline adherence to the three medications was similar across DHP and control employers, ranging from 64 to 69 %. In the first year after DHP implementation, predicted employer-level adherence for metformin (+4.9 percentage points, p = 0.017), statins (+4.8, p = 0.019), and ACE/ARBs (+4.4, p = 0.02) was higher with DHP purchase.LimitationsNon-randomized, observational study.ConclusionsThe Diabetes Health Plan, an innovative health plan that combines reduced cost-sharing and disease management with an up-front requirement of enrollee participation in his or her own health care, is associated with a modest improvement in medication adherence at 12 months.

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ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

Publications

ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

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