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      Hypertension and renin-angiotensin system blockers are not associated with expression of angiotensin-converting enzyme 2 (ACE2) in the kidney

      e1 , e1 , e1 , e1 , e2 , e2 , e3 , e1 , e1 , e4 , e5 , e6 , e7 , e8 , e9 , e6 , e10 , e5 , e11 , e12 , e13 , e14 , e15 , e1 , e16 , e6 , e1 , e16 , e17 , e1 , e16 , e18 , e19 , e4 , e3 , e20 , e21 , e22 , e2 , e3 , e19 , e1 , e16

      European Heart Journal

      Oxford University Press

      ACE2, Kidney, Hypertension, Renin-angiotensin system, Antihypertensive treatment, Transcriptome , Estimated glomerular filtration rate

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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.

          Graphical Abstract

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          Most cited references 59

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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              Endothelial cell infection and endotheliitis in COVID-19

              Cardiovascular complications are rapidly emerging as a key threat in coronavirus disease 2019 (COVID-19) in addition to respiratory disease. The mechanisms underlying the disproportionate effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities, however, remain incompletely understood.1, 2 SARS-CoV-2 infects the host using the angiotensin converting enzyme 2 (ACE2) receptor, which is expressed in several organs, including the lung, heart, kidney, and intestine. ACE2 receptors are also expressed by endothelial cells. 3 Whether vascular derangements in COVID-19 are due to endothelial cell involvement by the virus is currently unknown. Intriguingly, SARS-CoV-2 can directly infect engineered human blood vessel organoids in vitro. 4 Here we demonstrate endothelial cell involvement across vascular beds of different organs in a series of patients with COVID-19 (further case details are provided in the appendix). Patient 1 was a male renal transplant recipient, aged 71 years, with coronary artery disease and arterial hypertension. The patient's condition deteriorated following COVID-19 diagnosis, and he required mechanical ventilation. Multisystem organ failure occurred, and the patient died on day 8. Post-mortem analysis of the transplanted kidney by electron microscopy revealed viral inclusion structures in endothelial cells (figure A, B ). In histological analyses, we found an accumulation of inflammatory cells associated with endothelium, as well as apoptotic bodies, in the heart, the small bowel (figure C) and lung (figure D). An accumulation of mononuclear cells was found in the lung, and most small lung vessels appeared congested. Figure Pathology of endothelial cell dysfunction in COVID-19 (A, B) Electron microscopy of kidney tissue shows viral inclusion bodies in a peritubular space and viral particles in endothelial cells of the glomerular capillary loops. Aggregates of viral particles (arrow) appear with dense circular surface and lucid centre. The asterisk in panel B marks peritubular space consistent with capillary containing viral particles. The inset in panel B shows the glomerular basement membrane with endothelial cell and a viral particle (arrow; about 150 nm in diameter). (C) Small bowel resection specimen of patient 3, stained with haematoxylin and eosin. Arrows point to dominant mononuclear cell infiltrates within the intima along the lumen of many vessels. The inset of panel C shows an immunohistochemical staining of caspase 3 in small bowel specimens from serial section of tissue described in panel D. Staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections, indicating that apoptosis is induced in a substantial proportion of these cells. (D) Post-mortem lung specimen stained with haematoxylin and eosin showed thickened lung septa, including a large arterial vessel with mononuclear and neutrophilic infiltration (arrow in upper inset). The lower inset shows an immunohistochemical staining of caspase 3 on the same lung specimen; these staining patterns were consistent with apoptosis of endothelial cells and mononuclear cells observed in the haematoxylin-eosin-stained sections. COVID-19=coronavirus disease 2019. Patient 2 was a woman, aged 58 years, with diabetes, arterial hypertension, and obesity. She developed progressive respiratory failure due to COVID-19 and subsequently developed multi-organ failure and needed renal replacement therapy. On day 16, mesenteric ischaemia prompted removal of necrotic small intestine. Circulatory failure occurred in the setting of right heart failure consequent to an ST-segment elevation myocardial infarction, and cardiac arrest resulted in death. Post-mortem histology revealed lymphocytic endotheliitis in lung, heart, kidney, and liver as well as liver cell necrosis. We found histological evidence of myocardial infarction but no sign of lymphocytic myocarditis. Histology of the small intestine showed endotheliitis (endothelialitis) of the submucosal vessels. Patient 3 was a man, aged 69 years, with hypertension who developed respiratory failure as a result of COVID-19 and required mechanical ventilation. Echocardiography showed reduced left ventricular ejection fraction. Circulatory collapse ensued with mesenteric ischaemia, and small intestine resection was performed, but the patient survived. Histology of the small intestine resection revealed prominent endotheliitis of the submucosal vessels and apoptotic bodies (figure C). We found evidence of direct viral infection of the endothelial cell and diffuse endothelial inflammation. Although the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby causing lung injury, the ACE2 receptor is also widely expressed on endothelial cells, which traverse multiple organs. 3 Recruitment of immune cells, either by direct viral infection of the endothelium or immune-mediated, can result in widespread endothelial dysfunction associated with apoptosis (figure D). The vascular endothelium is an active paracrine, endocrine, and autocrine organ that is indispensable for the regulation of vascular tone and the maintenance of vascular homoeostasis. 5 Endothelial dysfunction is a principal determinant of microvascular dysfunction by shifting the vascular equilibrium towards more vasoconstriction with subsequent organ ischaemia, inflammation with associated tissue oedema, and a pro-coagulant state. 6 Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7, 8, 9, 10, 11 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.
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                Author and article information

                Journal
                Eur Heart J
                Eur Heart J
                eurheartj
                European Heart Journal
                Oxford University Press
                0195-668X
                1522-9645
                27 October 2020
                Affiliations
                [e1 ] Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, University of Manchester , Manchester, UK
                [e2 ] School of Health and Life Sciences, Federation University Australia , Ballarat, VIC, Australia
                [e3 ] Department of Cardiovascular Sciences, University of Leicester , Leicester, UK
                [e4 ] Department of Cellular Genetics, Wellcome Sanger Institute , Cambridge, UK
                [e5 ] Department of General, Vascular and Transplant Surgery, Medical University of Silesia , Katowice, Poland
                [e6 ] Department of Treatment of Obesity, Metabolic Disorders and Clinical Dietetics, Poznan University of Medical Sciences , Poznan, Poland
                [e7 ] Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences , Poznan, Poland
                [e8 ] Centre for Systems Genomics, School of BioSciences, The University of Melbourne , Parkville, VIC, Australia
                [e9 ] Department of Pathology, The University of Melbourne , Parkville, VIC, Australia
                [e10 ] Department of Transplantology and General Surgery Poznan, Collegium Medicum, Nicolaus Copernicus University , Bydgoszcz, Poland
                [e11 ] Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia , Zabrze, Poland
                [e12 ] Department of Health Care, Silesian Medical College , Katowice, Poland
                [e13 ] Department of Medicine and Cardiology, University of Melbourne, Melbourne, VIC, Australia
                [e14 ] Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester , Manchester, UK
                [e15 ] Royal Manchester Children’s Hospital and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust , Manchester, UK
                [e16 ] Division of Medicine and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust Manchester , Manchester, UK
                [e17 ] Division of Musculoskeletal & Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester , Manchester, UK
                [e18 ] Institute of Cardiovascular Sciences, University College London , London, UK
                [e19 ] Department of Physiology, University of Melbourne , Melbourne, VIC, Australia
                [e20 ] Leicester Biomedical Research Centre, National Institute for Health Research , Leicester, UK
                [e21 ] Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow , Glasgow, UK
                [e22 ] Department of Internal and Agricultural Medicine, Jagiellonian University College of Medicine , Kraków, Poland
                Author notes

                Xiao Jiang and James M Eales contributed equally to this work.

                Corresponding author. Tel: +44 161 275 0232, Email: maciej.tomaszewski@ 123456manchester.ac.uk
                Article
                ehaa794
                10.1093/eurheartj/ehaa794
                7665509
                © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 9
                Product
                Funding
                Funded by: British Heart Foundation, DOI 10.13039/501100000274;
                Award ID: PG/17/35/33001
                Award ID: PG/19/16/34270
                Funded by: Kidney Research UK, DOI 10.13039/501100000291;
                Award ID: RP_017_20180302
                Funded by: British Heart Foundation Personal Chair;
                Award ID: CH/13/2/30154
                Funded by: Manchester Academic Health Science Centre;
                Funded by: Medical University of Silesia, DOI 10.13039/100007771;
                Award ID: KNW-1-152/N/7/K
                Award ID: KNW-1-171/N/6/K
                Funded by: National Health and Medical Research project grant;
                Award ID: APP1104686
                Funded by: European Research Council, DOI 10.13039/100010663;
                Award ID: ERC-CoG-726318
                Funded by: ERA-CVD;
                Award ID: PLAQUEFIGHT/5/2018
                Funded by: National Health and Medical Research Council Program;
                Award ID: APP1055214
                Funded by: Medical Research Future Fund;
                Award ID: APP 1175865
                Funded by: Wellcome Trust, DOI 10.13039/100010269;
                Award ID: WT206194
                Funded by: Gates Cambridge Scholarship;
                Award ID: OPP1144
                Categories
                Clinical Research
                AcademicSubjects/MED00200
                Custom metadata
                PAP

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