The Pathophysiology of Long COVID Throughout the Renin-Angiotensin System

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2022 May 14

PMID 35566253

Authors

Shaymaa Khazaal

Julien Harb

Mohamad Rima

Cedric Annweiler

Yingliang Wu

Zhijian Cao

Ziad Abi Khattar

Christian Legros

Herve Kovacic

Ziad Fajloun

Jean-Marc Sabatier

Affiliations

Soon will be listed here.

Abstract

COVID-19 has expanded across the world since its discovery in Wuhan (China) and has had a significant impact on people's lives and health. Long COVID is a term coined by the World Health Organization (WHO) to describe a variety of persistent symptoms after acute SARS-CoV-2 infection. Long COVID has been demonstrated to affect various SARS-CoV-2-infected persons, independently of the acute disease severity. The symptoms of long COVID, like acute COVID-19, consist in the set of damage to various organs and systems such as the respiratory, cardiovascular, neurological, endocrine, urinary, and immune systems. Fatigue, dyspnea, cardiac abnormalities, cognitive and attention impairments, sleep disturbances, post-traumatic stress disorder, muscle pain, concentration problems, and headache were all reported as symptoms of long COVID. At the molecular level, the renin-angiotensin system (RAS) is heavily involved in the pathogenesis of this illness, much as it is in the acute phase of the viral infection. In this review, we summarize the impact of long COVID on several organs and tissues, with a special focus on the significance of the RAS in the disease pathogenesis. Long COVID risk factors and potential therapy approaches are also explored.

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References

Myall K, Mukherjee B, Castanheira A, Lam J, Benedetti G, Mak S . Persistent Post-COVID-19 Interstitial Lung Disease. An Observational Study of Corticosteroid Treatment. Ann Am Thorac Soc. 2021; 18(5):799-806. PMC: 8086530. DOI: 10.1513/AnnalsATS.202008-1002OC. View

Wu Z, McGoogan J . Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323(13):1239-1242. DOI: 10.1001/jama.2020.2648. View

Darley D, Dore G, Cysique L, Wilhelm K, Andresen D, Tonga K . Persistent symptoms up to four months after community and hospital-managed SARS-CoV-2 infection. Med J Aust. 2021; 214(6):279-280. PMC: 8014234. DOI: 10.5694/mja2.50963. View

Theoharides T, Conti P . COVID-19 and Multisystem Inflammatory Syndrome, or is it Mast Cell Activation Syndrome?. J Biol Regul Homeost Agents. 2020; 34(5):1633-1636. DOI: 10.23812/20-EDIT3. View

Chung M, Zidar D, Bristow M, Cameron S, Chan T, Harding 3rd C . COVID-19 and Cardiovascular Disease: From Bench to Bedside. Circ Res. 2021; 128(8):1214-1236. PMC: 8048382. DOI: 10.1161/CIRCRESAHA.121.317997. View

Navale A, Paranjape A . Glucose transporters: physiological and pathological roles. Biophys Rev. 2017; 8(1):5-9. PMC: 5425736. DOI: 10.1007/s12551-015-0186-2. View

DArdes D, Boccatonda A, Rossi I, Guagnano M, Santilli F, Cipollone F . COVID-19 and RAS: Unravelling an Unclear Relationship. Int J Mol Sci. 2020; 21(8). PMC: 7215550. DOI: 10.3390/ijms21083003. View

Hulme K, Gallo L, Short K . Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination?. Front Microbiol. 2017; 8:861. PMC: 5438975. DOI: 10.3389/fmicb.2017.00861. View

Zhang L, Richards A, Barrasa M, Hughes S, Young R, Jaenisch R . Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues. Proc Natl Acad Sci U S A. 2021; 118(21). PMC: 8166107. DOI: 10.1073/pnas.2105968118. View

10.

Bowe B, Xie Y, Xu E, Al-Aly Z . Kidney Outcomes in Long COVID. J Am Soc Nephrol. 2021; 32(11):2851-2862. PMC: 8806085. DOI: 10.1681/ASN.2021060734. View

11.

Mukherjee R, Bhattacharya A, Bojkova D, Mehdipour A, Shin D, Khan K . Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection. J Biol Chem. 2021; 297(2):100925. PMC: 8241579. DOI: 10.1016/j.jbc.2021.100925. View

12.

Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer J . Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002; 109(11):1417-27. PMC: 150992. DOI: 10.1172/JCI14276. View

13.

Chen L, Li X, Chen M, Feng Y, Xiong C . The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc Res. 2020; 116(6):1097-1100. PMC: 7184507. DOI: 10.1093/cvr/cvaa078. View

14.

Lamb L, Dhar N, Timar R, Wills M, Dhar S, Chancellor M . COVID-19 inflammation results in urine cytokine elevation and causes COVID-19 associated cystitis (CAC). Med Hypotheses. 2020; 145:110375. PMC: 7644255. DOI: 10.1016/j.mehy.2020.110375. View

15.

Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong J, Turner A . Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020; 126(10):1456-1474. PMC: 7188049. DOI: 10.1161/CIRCRESAHA.120.317015. View

16.

Greenhalgh T, Knight M, ACourt C, Buxton M, Husain L . Management of post-acute covid-19 in primary care. BMJ. 2020; 370:m3026. DOI: 10.1136/bmj.m3026. View

17.

Unnikrishnan R, Misra A . Diabetes and COVID19: a bidirectional relationship. Nutr Diabetes. 2021; 11(1):21. PMC: 8223528. DOI: 10.1038/s41387-021-00163-2. View

18.

Eshak N, Abdelnabi M, Ball S, Elgwairi E, Creed K, Test V . Dysautonomia: An Overlooked Neurological Manifestation in a Critically ill COVID-19 Patient. Am J Med Sci. 2020; 360(4):427-429. PMC: 7366085. DOI: 10.1016/j.amjms.2020.07.022. View

19.

Annweiler C, Papon N, Sabatier J, Barre J . DAMPening Severe COVID-19 with Dexamethasone. Infect Disord Drug Targets. 2021; 22(2):e270821195910. DOI: 10.2174/1871526521999210827142839. View

20.

Fagyas M, Fejes Z, Suto R, Nagy Z, Szekely B, Pocsi M . Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients. Int J Infect Dis. 2021; 115:8-16. PMC: 8613979. DOI: 10.1016/j.ijid.2021.11.028. View