Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2021  |  Volume : 19  |  Issue : 3  |  Page : 218-219

The downregulation of angiotensin-converting enzyme 2 expression may be associated with depression and anxiety among patients with severe acute respiratory syndrome Coronavirus 2

Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy

Date of Submission02-May-2021
Date of Decision10-May-2021
Date of Acceptance13-May-2021
Date of Web Publication05-Jul-2021

Correspondence Address:
Dr. Chidiebere Emmanuel Okechukwu
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmi.cmi_47_21

Rights and Permissions

How to cite this article:
Okechukwu CE. The downregulation of angiotensin-converting enzyme 2 expression may be associated with depression and anxiety among patients with severe acute respiratory syndrome Coronavirus 2. Curr Med Issues 2021;19:218-9

How to cite this URL:
Okechukwu CE. The downregulation of angiotensin-converting enzyme 2 expression may be associated with depression and anxiety among patients with severe acute respiratory syndrome Coronavirus 2. Curr Med Issues [serial online] 2021 [cited 2021 Dec 4];19:218-9. Available from: https://www.cmijournal.org/text.asp?2021/19/3/218/320657


According to a study conducted in Brazil, anxiety, and depression were the most prevalent psychiatric symptoms of coronavirus disease 2019 (COVID-19) in the general population.[1] Several patients with COVID-19 often battle with depression and anxiety.[2],[3] Depression and anxiety are associated with noncompliance to medical treatment.[4],[5] A positive correlation was found between depression, anxiety, and perceived stress among hospitalized patients with COVID-19.[6]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes COVID-19.[7] The angiotensin-converting enzyme 2 (ACE2), is the entry receptor for SARS-CoV-2. SARS-CoV-2 competes with angiotensin II (Ang II) for ACE2. The SARS-CoV-2 penetrates the host cell through communicating with the ACE2 receptor through its spike protein, followed by the downregulation of ACE2 expression which eventually upregulates Ang II. The Ang II is a product of the renin-angiotensin system formed by the cleavage of Ang I by the enzyme ACE. The upregulated Ang II interacts with its receptor Ang II receptor type 1 (AT1R) and modifies the gene expression of several inflammatory cytokines through the nuclear factor kappa-light-chain-enhancer of activated B cells signaling. This Ang II/AT1R interaction also effects the macrophage activation that in turn produces the inflammatory cytokines, thus inducing acute respiratory distress syndrome. However, some metalloproteases (e.g., A disintegrin and metalloprotease 17) breaks down proinflammatory cytokines and ACE2 receptors to the soluble form which facilitates loss of the protective function of surface ACE2 and may increase SARS-CoV-2 pathogenesis.[8] The binding of SARS-CoV-2 with ACE2, and the subsequent downregulation of ACE2 activities, significantly reduce the expression of ACE2 in the cell membranes.[9]

The interactions between angiotensin and dopamine receptors have been observed in cells containing both angiotensin and dopamine receptors in peripheral tissues,[10],[11] and in the basal ganglia, where counterregulatory interaction between dopamine and angiotensin receptors were observed in the striatum and substantia nigra.[12] The receptor-mediated interactions may be responsible for the modulation of dopamine-mediated behavioral responses by antagonists of the AT1R and inhibitors of ACE.[13] Ang II type 2 receptor stimulation reduced dopamine synthesis in the rat striatum.[14] Animals with genetic alterations in the expression of ACE2 develop a distinct pattern of phenotypes which include behavioral dysfunctions, impairments in serotonin synthesis, and neurogenesis.[15]

ACE2 and dopa decarboxylase (DDC) co-express and co-regulate in non-neuronal cell types.[16] Reduction in ACE2 expression may also decrease DDC expression, thus altering the biosynthesis of dopamine and serotonin, because DDC catalyzes the biosynthesis of dopamine and serotonin.[17] The possible biological mechanism linking ACE2 down-regulation with concomitant downregulation of DDC remains unclear. Low levels of serotonin and dopamine are associated with depression and anxiety.[18] SARS-CoV-2 induced altered expression of ACE2 may as well induce DDC dysfunction, which could possibly decrease the levels of monoamine neurotransmitters in patients with COVID-19.[19]

This is supported by studies in ACE2 knockout mice which showed that these mice produced significantly lower levels of serotonin. This demonstrates that the reduction of ACE2 may possibly decrease brain serotonin levels.[20] According to the multi experiment matrix, an advanced web tool that integrates and merge relationship ties between messenger RNA levels across human microarray datasets, the gene that presented the most statistically significant co-expression relationship with ACE2 is the DDC gene.[21]

DDC as a key enzyme of the dopamine and the serotonin pathways converts L-3,4-dihydroxyphenylalanine to dopamine and L-5-hydroxytryptophan to serotonin.[22] ACE2 potential coregulation with DDC could signify a possible biological association between the ACE2-mediated synthesis of angiotensin (1–7) and the DDC-mediated synthesis of dopamine and serotonin. Although, dopamine and angiotensin systems directly counterregulate each other in renal cells.[22]

In conclusion, SARS-CoV-2 downregulation of ACE2 expression may possibly reduce DDC expression, because ACE2 and DDC co-express and co-regulate in several cell types, which could decrease the levels of serotonin and dopamine in patients with COVID-19, resulting to depression and anxiety. However, further studies are needed to substantiate the biological relationship between the SARS-CoV-2 induced downregulation of ACE2, and the prevalence of depression and anxiety among patients with COVID-19.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Goularte JF, Serafim SD, Colombo R, Hogg B, Caldieraro MA, Rosa AR. COVID-19 and mental health in Brazil: Psychiatric symptoms in the general population. J Psychiatr Res 2021;132:32-7.  Back to cited text no. 1
Dai LL, Wang X, Jiang TC, Li PF, Wang Y, Wu SJ, et al. Anxiety and depressive symptoms among COVID-19 patients in Jianghan Fangcang Shelter Hospital in Wuhan, China. PLoS One 2020;15:e0238416.  Back to cited text no. 2
Dorman-Ilan S, Hertz-Palmor N, Brand-Gothelf A, Hasson-Ohayon I, Matalon N, Gross R, et al. Anxiety and Depression Symptoms in COVID-19 isolated patients and in their relatives. Front Psychiatry 2020;11:581598.  Back to cited text no. 3
DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: Meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med 2000;160:2101-7.  Back to cited text no. 4
Alcántara C, Edmondson D, Moise N, Oyola D, Hiti D, Kronish IM. Anxiety sensitivity and medication nonadherence in patients with uncontrolled hypertension. J Psychosom Res 2014;77:283-6.  Back to cited text no. 5
Zandifar A, Badrfam R, Yazdani S, Arzaghi SM, Rahimi F, Ghasemi S, et al. Prevalence and severity of depression, anxiety, stress and perceived stress in hospitalized patients with COVID-19 [published online ahead of print, 2020 Oct 29]. J Diabetes Metab Disord. 2020;19:1-8. doi:10.1007/s40200-020-00667-1.  Back to cited text no. 6
Bourgonje AR, Abdulle AE, Timens W, Hillebrands JL, Navis GJ, Gordijn SJ, et al. Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19). J Pathol 2020;251:228-48.  Back to cited text no. 7
Banu N, Panikar SS, Leal LR, Leal AR. Protective role of ACE2 and its downregulation in SARS-CoV-2 infection leading to Macrophage Activation Syndrome: Therapeutic implications. Life Sci 2020;256:117905.  Back to cited text no. 8
Zemlin AE, Wiese OJ. Coronavirus disease 2019 (COVID-19) and the renin-angiotensin system: A closer look at angiotensin-converting enzyme 2 (ACE2). Ann Clin Biochem 2020;57:339-50.  Back to cited text no. 9
Garrido-Gil P, Rodriguez-Perez AI, Dominguez-Meijide A, Guerra MJ, Labandeira-Garcia JL. Bidirectional neural interaction between central dopaminergic and gut lesions in Parkinson's disease models. Mol Neurobiol 2018;55:7297-316.  Back to cited text no. 10
Campos J, Pacheco R. Involvement of dopaminergic signaling in the cross talk between the renin-angiotensin system and inflammation. Semin Immunopathol 2020;42:681-96.  Back to cited text no. 11
Villar-Cheda B, Dominguez-Meijide A, Valenzuela R, Granado N, Moratalla R, Labandeira-Garcia JL. Aging-related dysregulation of dopamine and angiotensin receptor interaction. Neurobiol Aging 2014;35:1726-38.  Back to cited text no. 12
Brown DC, Steward LJ, Ge J, Barnes NM. Ability of angiotensin II to modulate striatal dopamine release via the AT1 receptor in vitro and in vivo. Br J Pharmacol 1996;118:414-20.  Back to cited text no. 13
Mertens B, Vanderheyden P, Michotte Y, Sarre S. Direct angiotensin II type 2 receptor stimulation decreases dopamine synthesis in the rat striatum. Neuropharmacology 2010;58:1038-44.  Back to cited text no. 14
Alenina N, Bader M. ACE2 in brain physiology and pathophysiology: Evidence from transgenic animal models. Neurochem Res 2019;44:1323-9.  Back to cited text no. 15
Attademo L, Bernardini F. Are dopamine and serotonin involved in COVID-19 pathophysiology? Eur J Psychiatry 2021;35:62-3.  Back to cited text no. 16
Blum K, Cadet JL, Baron D, Badgaiyan RD, Brewer R, Modestino EJ, et al. Putative COVID- 19 Induction of Reward Deficiency Syndrome (RDS) and associated behavioral addictions with potential concomitant dopamine depletion: Is COVID-19 social distancing a double edged sword? Subst Use Misuse 2020;55:2438-42.  Back to cited text no. 17
Liu Y, Zhao J, Guo W. Emotional Roles of Mono-Aminergic Neurotransmitters in Major Depressive Disorder and Anxiety Disorders. Front Psychol 2018;9:2201.  Back to cited text no. 18
Riederer P, Ter Meulen V. Coronaviruses: A challenge of today and a call for extended human postmortem brain analyses. J Neural Transm (Vienna) 2020;127:1217-28.  Back to cited text no. 19
Klempin F, Mosienko V, Matthes S, Villela DC, Todiras M, Penninger JM, et al. Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response. Cell Mol Life Sci 2018;75:3625-34.  Back to cited text no. 20
Adler P, Kolde R, Kull M, Tkachenko A, Peterson H, Reimand J, et al. Mining for coexpression across hundreds of datasets using novel rank aggregation and visualization methods. Genome Biol 2009;10:R139.  Back to cited text no. 21
Gildea JJ. Dopamine and angiotensin as renal counterregulatory systems controlling sodium balance. Curr Opin Nephrol Hypertens 2009;18:28-32.  Back to cited text no. 22


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article

 Article Access Statistics
    PDF Downloaded46    
    Comments [Add]    

Recommend this journal