Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19
Flavio A. Cadegiani
Carlos G. Wambier3 
Andy Goren- 1Department of Endocrinology, Federal University of São Paulo, São Paulo, Brazil
- 2Corpometria Institute, Brasília, Brazil
- 3Department of Dermatology, Warren Alpert Medical School of Brown University, Providence, RI, United States
- 4Applied Biology Inc., Irvine, CA, United States
Introduction
At the onset of the COVID-19 pandemic, mortality following infection of severe acute respiratory coronavirus (SARS-CoV-2) was thought to be solely associated with aging and pre-existing conditions; however, as the pandemic ensued, several large scale epidemiological observations eluded to additional atypical risk factors, particularly hypertension, obesity, and male gender (1–11).
SARS-CoV-2: Current Knowledge on the Mechanisms of Action
The peculiarities and complexity of SARS-CoV-2 infection patterns precluded definitive findings regarding the mechanisms of infectivity. Current literature suggests that angiotensin-converting enzyme-2 (ACE2) receptor and transmembrane serine protease 2 (TMPRSS2) are the key for SARS-CoV-2 cell entry (12–19). While ACE2 is the coupling site of the spike protein of SARS-CoV-2, TMPRSS2 facilitates SARS-CoV-2 spikes and ACE2 for viral cell entry. Although ACE2 expression is present diffusely, up to 80% of its expression is located in the type-2 pneumocytes (12, 17), which may explain why COVID-19 is predominantly pulmonary, although SARS-COV-2 may affect any organ and system. TMPRSS2 activity is modulated by androgens, which may justify why males are overrepresented among severe COVID-19 infected patients (20).
Current understanding of SARS-CoV-2 allows the division of COVID-19 into two phases (12–18). In a first, early phase, which corresponds to the period of SARS-CoV-2 cell entry, lung membrane-attached ACE2 expression seems to be positively correlated with virus infectivity, while the balance between circulating ACE2, that could protect from lung infectivity by coupling with SARS-CoV-2 and precluding from the entry into the pneumocytes (13–16), and membrane-attached ACE2, may also be relevant.
In a second phase, represented by the inflammatory and immunological responses to SARS-CoV-2 infection, ACE2 is downregulated due to the entry into cell cytoplasm when coupled with the virus. In opposition to the first phase, in the second phase, lung-attached ACE2 expression may be positively correlated with better clinical outcomes, since ACE2 may limit the cytokine storm that underlies the Acute Respiratory Distress Syndrome (ARDS) in COVID-19, while the balance between proinflammatory angiotensin II–angiotensin receptor type 1 (AT1) axis, and the anti-inflammatory angiotensin 1–7—G-coupled Mas receptor (angiotensin 1–7 receptor) axis may also be crucial for level of severity of the second phase (13, 15–19).
SARS-CoV-2: The Link Between Mechanisms of Action and Risk Factors
The Renin-Angiotensin-Aldosterone System (RAAS) has been shown to be central in COVID-19, since three of the key modulators of SARS-CoV-2 infectivity–angiotensin 1–7, ACE2, and AT1—belong to the RAAS, in addition to the TMPRSS2 expression (12–19).
Disruption of RAAS and ACE2 expression abnormalities are likely the underlying mechanism that links hypertension and obesity as important risk factors for COVID-19 (21–29). Conversely, TMPRSS2 overexpression in response to exposure to androgens may justify the higher occurrence of COVID-19 complications in males (30–33), which can be reinforced by the fact that males under androgen deprivation therapies such as for prostate cancer may experiment decreased risk for ARDS when compared to age-, sex-, and comorbidities-matched subjects (33).
A pro-thrombotic state, and endothelial, hematological, kidney, hepatic, cardiovascular, gonadal, neurological, and gastrointestinal manifestations in COVID-19 are at least partially mediated by ACE2 and TMPRSS2 expressions (34–60).
In summary, aberrancies in ACE2 expression, unbalance between angiotensin II and angiotensin 1–7 levels, and overexpression of TMPRS22 seem to be key factors for the severity of clinical manifestations in COVID-19.
Spironolactone as a Candidate Against COVID-19
Drugs that address ACE2, any sight of the RAAS, or TMPRSS2 expression are potential candidates for COVID-19. In this context, the use of old drugs against COVID-19 may present major potential benefits over novel drugs for some reasons, including: (1) The well-established long-term safety profile (2) Extensively described risks and contraindications, which allows to prevent its use when contraindicated and monitor for risks directedly; and (3) The lower cost of old, non-patented drugs allows its massive use in public health systems, when clinically indicated.
These observations combined with our understanding of SARS-CoV-2 molecular mechanism of infectivity lead us to believe that spironolactone is an ideal candidate drug for the prophylactic treatment of SARS-CoV-2.
Spironolactone is a safe and well-tolerated anti-hypertensive and anti-androgenic drug used since 1959, that is effective to maintain normal blood levels (61–63), address heart function, and provide cardio- and renoprotection (64–68).
While spironolactone is a safe and unexpensive option, it may act in multiple sites against COVID-19, including: (1) Favorable patterns of ACE2 expression, including potential increase of circulating ACE2, enhancing its potential protective role in SARS-CoV-2, once plasma ACE2 may couple to SARS-CoV-2 and avoid its entry in the cells (24, 69–74); (2) Downregulation of the androgen-mediated TMPRSS2 due to its antiandrogenic activity (75–77), without the adverse events of male sexual castration; (3) Mitigation of the deleterious effects of obesity on the RAAS, possibly reducing obesity-related COVID-19 complications (78, 79); (4) Direct anti-inflammatory and anti-viral effects that could directly avoid pulmonary complications of COVID-19 (80–90).
Hence, spironolactone meets corresponding epidemiological data, mechanistical plausibility, and sufficient safety profile to become a candidate against COVID-19.
For the proper management of spironolactone during COVID-19, since spironolactone mostly targets the virus entry in the cells, which is the hallmark of the first phase of Covid-19, spironolactone should be preferably started during the earlier stages of the infection, prior to the complications of respiratory manifestations, but could also be employed in the second phase, when the inflammatory and immunologic responses become clinically relevant, due to its anti-inflammatory effects (91).
Conclusion
Abnormal ACE2 expression, angiotensin II and angiotensin 1–7 imbalance, and TMPRSS2 androgen-mediated overactivity seem to be key regulators of SARS-CoV-2 infectivity, in accordance with epidemiological observations of hypertension, obesity, and male sex as being major risk factors. Since spironolactone is a long used safe drug that exhibits concurrent actions in the modulation of ACE2 expression that could avoid SARS-CoV-2 cell entry, attenuation of the harms caused by the overexpression of angiotensin II-AT-1 axis, discloses anti-androgenic activity that can decrease viral priming through TMPRSS2 activity, and has anti-inflammatory effects in the lungs, spironolactone seems to be a plausible candidate for the prophylactic and early treatment of SARS-CoV-2.
Author Contributions
FC, CW, and AG developed the underlying theories on the present paper, wrote, and reviewed the manuscript in its final format for submission. All authors contributed to the article and approved the submitted version.
Conflict of Interest
AG is the CEO of the company Applied Biology Inc (Irvine, CA, USA). CW is part of the medical board of the company Applied Biology Inc (Irvine, CA, USA). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We acknowledge all researchers who have provided insightful and helpful information aiming to overcome the COVID-19 pandemic, as well as all front-line health providers who are directly dealing with COVID-19 infected patients, exposing themselves at risk for this potentially severe infection.
References
1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. (2020) 395:1054–62. doi: 10.1016/S0140-6736(20)30566-3
2. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The incubation period of Coronavirus Disease (2019) (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med. (2020) 172:577–82. doi: 10.7326/M20-0504
3. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019. Pneumonia in Wuhan, China. JAMA Intern Med. (2020) 180:1–11. doi: 10.1001/jamainternmed.2020.0994
4. Liu W, Tao ZW, Wang L, Yuan ML, Liu K, Zhou L, et al. Analysis of factors associated with disease outcomes in hospitalized patients with 2019 novel coronavirus disease. Chin Med J. (2020) 133:1032–8. doi: 10.1097/CM9.0000000000000775
5. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. (2020) 8:e21. doi: 10.1016/S2213-2600(20)30116-8
6. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. China medical treatment expert group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. (2020) 382:1708–20. doi: 10.1101/2020.02.06.20020974
7. Hajifathalian K, Kumar S, Newberry C, Shah S, Fortune B, Krisko T, et al. Obesity is associated with worse outcomes in COVID-19: analysis of Early data from New York City. Obesity. (2020). doi: 10.1002/oby.22923. [Epub ahead of print].
8. Kalligeros M, Shehadeh F, Mylona EK, Benitez G, Beckwith CG, Chan PA, et al. Association of obesity with disease severity among patients with coronavirus disease (2019). Obesity. (2020) 28:1200–4. doi: 10.1002/oby.22859
9. Palaiodimos L, Kokkinidis DG, Li W, Karamanis D, Ognibene J, Arora S, et al. Severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with COVID-19 in the Bronx, New York. Metabolism. (2020) 108:154262. doi: 10.1016/j.metabol.2020.154262
10. Goren A, McCoy J, Wambier CG, Vano-Galvan S, Shapiro J, Dhurat R, et al. What does androgenetic alopecia have to do with COVID-19? An insight into a potential new therapy. Dermatol Ther. (2020) 1:e13365. doi: 10.1111/dth.13365
11. Goren A, Vaño-Galván S, Wambier CG, McCoy J, Gomez-Zubiaur A, Moreno-Arrones OM, et al. A preliminary observation: male pattern hair loss among hospitalized COVID-19 patients in Spain - a potential clue to the role of androgens in COVID-19 severity. J Cosmet Dermatol. (2020) 19:1545–7. doi: 10.1111/jocd.13443
12. Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus: a first step in understanding SARS pathogenesis. J Pathol. (2004) 203:631–7. doi: 10.1002/path.1570
13. 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. doi: 10.1002/path.5471
14. Li Y, Zhou W, Yang L, You R. Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor. Pharmacol Res. (2020) 157:104833. doi: 10.1016/j.phrs.2020.104833
15. Song J, Li Y, Huang X, Chen Z, Li Y, Liu C, et al. Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2. J Med Virol. (2020) 1–11. doi: 10.1002/jmv.26045. [Epub ahead of print].
16. Imai Y, Kuba K, Ohto-Nakanishi T, Penninger JM. Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circ J. (2010) 74:405–10. doi: 10.1253/circj.CJ-10-0045
17. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. (2005) 11:875–9. doi: 10.1038/nm1267
18. Hoffmann M, Kleine-Wever H, Kruger N, Muller M, Drotsten C, Pholhlmann S. The novel coronavirus (2019) (2019-nCoV) uses the SARS coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry in target cells. Cell. (2020) 181:1–10. doi: 10.1101/2020.01.31.929042
19. Ortega JT, Serrano ML, Pujol FH, Rangel HR. Role of changes in SARS-CoV-2 spike protein in the interaction with the human ACE2 receptor: an in silico analysis. EXCLI J. (2020) 19:410–7. doi: 10.17179/excli2020-1167
20. Wambier CG, Goren A. SARS-COV-2 infection is likely to be androgen mediated. J Am Acad Dermatol. (2020) 83:308–9. doi: 10.1016/j.jaad.2020.04.032R
21. Pirola CJ, Sookoian S. Estimation of RAAS-Inhibitor effect on the COVID-19 outcome: a meta-analysis. J Infect. (2020). doi: 10.1016/j.jinf.2020.05.052. [Epub ahead of print].
22. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia. (2020) 63:1500–15. doi: 10.1007/s00125-020-05180-x
23. Groß S, Jahn C, Cushman S, Bär C, Thum T. SARS-CoV-2 receptor ACE2-dependent implications on the cardiovascular system: from basic science to clinical implications. J Mol Cell Cardiol. (2020) 144:47–53. doi: 10.1016/j.yjmcc.2020.04.031
24. South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. (2020) 318:H1084–90. doi: 10.1152/ajpheart.00217.2020
25. Engeli S, Böhnke J, Gorzelniak K, Janke J, Schling P, Bader M, et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. (2005) 45:356–62. doi: 10.1161/01.HYP.0000154361.47683.d3
26. Pinheiro TA, Barcala-Jorge AS, Andrade JMO, Pinheiro TA, Ferreira ECN, Crespo TS, et al. Obesity and malnutrition similarly alter the renin-angiotensin system and inflammation in mice and human adipose. J Nutr Biochem. (2017) 48:74–82. doi: 10.1016/j.jnutbio.2017.06.008
27. Frantz EDC, Giori IG, Machado MV, Magliano DC, Freitas FM, Andrade MSB, et al. High, but not low, exercise volume shifts the balance of renin-angiotensin system toward ACE2/Mas receptor axis in skeletal muscle in obese rats. Am J Physiol Endocrinol Metab. (2017) 313:E473–82. doi: 10.1152/ajpendo.00078.2017
28. Nagase M, Fujita T. Mineralocorticoid receptor activation in obesity hypertension. Hypertens Res. (2009) 32:649–57. doi: 10.1038/hr.2009.86
29. Jing F, Mogi M, Horiuchi M. Role of renin-angiotensin-aldosterone system in adipose tissue dysfunction. Mol Cell Endocrinol. (2013) 378:23–8. doi: 10.1016/j.mce.2012.03.005
30. Gebhard C, Regitz-Zagrosek V, Neuhauser HK, Morgan R, Klein SL. Impact of sex and gender on COVID-19 outcomes in Europe. Biol Sex Differ. (2020) 11:29. doi: 10.1186/s13293-020-00304-9
31. La Vignera S, Cannarella R, Condorelli RA, Torre F, Aversa A, Calogero AE. Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D. Int J Mol Sci. (2020) 21:2948. doi: 10.3390/ijms21082948
32. Wambier CG, Goren A, Vaño-Galván S, Ramos PM, Ossimetha A, Nau G, et al. Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev Res. (2020). doi: 10.1002/ddr.21688. [Epub ahead of print].
33. Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, et al. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (n = 4532). Ann Oncol. (2020). doi: 10.1016/j.annonc.2020.04.479. [Epub ahead of print].
34. Baig AM, Khaleeq A, Ali U, Syeda H. Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms. ACS Chem Neurosci. (2020) 11:995–8. doi: 10.1021/acschemneuro.0c00122
35. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. (2020) 92:552–5. doi: 10.1002/jmv.25728
36. Conde Cardona G, Quintana Pájaro LD, Quintero Marzola ID, Ramos Villegas Y, Moscote Salazar LR. Neurotropism of SARS-CoV 2: mechanisms and manifestations. J Neurol Sci. (2020) 412:116824. doi: 10.1016/j.jns.2020.116824
37. Natoli S, Oliveira V, Calabresi P, Maia LF, Pisani A. Does SARS-Cov-2 invade the brain? Translational lessons from animal models. Eur J Neurol. (2020). doi: 10.1111/ene.14277. [Epub ahead of print].
38. Helms J, Kremer S, Merdji H, Clere-Jehl R, Schenck M, Kummerlen C, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. (2020) 382:2268–70. doi: 10.1056/NEJMc2008597
39. Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, Fang Z, et al. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut. (2020) 69:997–1001. doi: 10.1136/gutjnl-2020-321013
40. Cheung KS, Hung IFN, Chan PPY, Lung KC, Tso E, Liu R, et al. Gastrointestinal manifestations of SARS-CoV-2 infection and virus load in fecal samples from a Hong Kong Cohort: systematic review and meta-analysis. Gastroenterology. (2020). doi: 10.1053/j.gastro.2020.03.065. [Epub ahead of print].
41. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology. (2020) 158:1831–3.e3. doi: 10.1053/j.gastro.2020.02.055
42. Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. (2020) 34:e212–3. doi: 10.1111/jdv.16387
43. Mungmunpuntipantip R, Wiwanitkit V. COVID-19 and cutaneous manifestations. J Eur Acad Dermatol Venereol. (2020) 34:e246. doi: 10.1111/jdv.16483
44. Zhu H, Rhee JW, Cheng P, Waliany S, Chang A, Witteles RM, et al. Cardiovascular complications in patients with COVID-19: consequences of viral toxicities and host immune response. Curr Cardiol Rep. (2020) 22:32. doi: 10.1007/s11886-020-01302-4
45. Kim IC, Kim JY, Kim HA, Han S. COVID-19-related myocarditis in a 21-year-old female patient. Eur Heart J. (2020) 41:1859. doi: 10.1093/eurheartj/ehaa288
46. Kochi AN, Tagliari AP, Forleo GB, Fassini GM, Tondo C. Cardiac and arrhythmic complications in patients with COVID-19. J Cardiovasc Electrophysiol. (2020) 31:1003–8. doi: 10.1111/jce.14479
47. Zeng JH, Liu YX, Yuan J, Wang FX, Wu WB, Li JX, et al. First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection. (2020) 10:1–5. doi: 10.1007/s15010-020-01424-5
48. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. (2020) 40:998–1004. doi: 10.1111/liv.14435
49. Lee IC, Huo TI, Huang YH. Gastrointestinal and liver manifestations in patients with COVID-19. J Chin Med Assoc. (2020) 83:521–3. doi: 10.1097/JCMA.0000000000000319
50. Musa S. Hepatic and gastrointestinal involvement in coronavirus disease (2019) (COVID-19): what do we know till now? Arab J Gastroenterol. (2020) 21:3–8. doi: 10.1016/j.ajg.2020.03.002
51. Fanelli V, Fiorentino M, Cantaluppi V, Gesualdo L, Stallone G, Ronco C, et al. Acute kidney injury in SARS-CoV-2 infected patients. Crit Care. (2020) 24:155. doi: 10.1186/s13054-020-02872-z
52. Chu KH, Tsang WK, Tang CS, Lam MF, Lai FM, To KF, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int. (2005) 67:698–705. doi: 10.1111/j.1523-1755.2005.67130.x
53. Abobaker A, Raba AA. Does COVID-19 affect male fertility? World J Urol. (2020) 21:1–2. doi: 10.1007/s00345-020-03208-w
54. Cardona Maya WD, Du Plessis SS, Velilla PA. SARS-CoV-2 and the testis: similarity with other viruses and routes of infection. Reprod Biomed Online. (2020) 40:763–4. doi: 10.1016/j.rbmo.2020.04.009
55. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. (2020) 191:145–7. doi: 10.1016/j.thromres.2020.04.013
56. Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, et al. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. (2020) 18:1743–6. doi: 10.1111/jth.14869
57. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. (2020) 18:1738–42. doi: 10.1111/jth.14850
58. Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. (2020) 18:1421–4. doi: 10.1111/jth.14830
59. Rotzinger DC, Beigelman-Aubry C, von Garnier C, Qanadli SD. Pulmonary embolism in patients with COVID-19: time to change the paradigm of computed tomography. Thromb Res. (2020) 190:58–9. doi: 10.1016/j.thromres.2020.04.011
60. Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol. (2020) 127:104362. doi: 10.1016/j.jcv.2020.104362
61. Georgianos PI, Vaios V, Eleftheriadis T, Zebekakis P, Liakopoulos V. Mineralocorticoid antagonists in ESRD: an overview of clinical trial evidence. Curr Vasc Pharmacol. (2017) 15:599–606. doi: 10.2174/1570161115666170201113817
62. Hermidorff MM, Faria Gde O, Amâncio Gde C, de Assis LV, Isoldi MC. Non-genomic effects of spironolactone and eplerenone in cardiomyocytes of neonatal Wistar rats: do they evoke cardioprotective pathways? Biochem Cell Biol. (2015) 93:83–93. doi: 10.1139/bcb-2014-0110
63. Cadegiani FA. Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension? Am J Physiol Endocrinol Metab. (2020) 318:E587–8. doi: 10.1152/ajpendo.00136.2020
64. Nakano S, Kobayashi N, Yoshida K, Ohno T, Matsuoka H. Cardioprotective mechanisms of spironolactone associated with the angiotensin-converting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats. Hypertens Res. (2005) 28:925–36. doi: 10.1291/hypres.28.925
65. Dieterich HA, Wendt C, Saborowski F. Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure. Fiziol Cheloveka. (2005) 31:97–105. doi: 10.1007/s10747-005-0119-8
66. Taira M, Toba H, Murakami M, Iga I, Serizawa R, Murata S, et al. Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats. Eur J Pharmacol. (2008) 589:264–71. doi: 10.1016/j.ejphar.2008.06.019
67. Schjoedt KJ. The renin-angiotensin-aldosterone system and its blockade in diabetic nephropathy: main focus on the role of aldosterone. Dan Med Bull. (2011) 58:B4265.
68. Kong EL, Zhang JM, An N, Tao Y, Yu WF, Wu FX. Spironolactone rescues renal dysfunction in obstructive jaundice rats by upregulating ACE2 expression. J Cell Commun Signal. (2019) 13:17–26. doi: 10.1007/s12079-018-0466-2
69. Takeda Y, Zhu A, Yoneda T, Usukura M, Takata H, Yamagishi M. Effects of aldosterone and angiotensin II receptor blockade on cardiac angiotensinogen and angiotensin-converting enzyme 2 expression in Dahl salt-sensitive hypertensive rats. Am J Hypertens. (2007) 20:1119–24. doi: 10.1016/j.amjhyper.2007.05.008
70. Zhu A, Yoneda T, Demura M, Karashima S, Usukura M, Yamagishi M, et al. Effect of mineralocorticoid receptor blockade on the renal renin-angiotensin system in Dahl salt-sensitive hypertensive rats. J Hypertens. (2009) 27:800–5. doi: 10.1097/HJH.0b013e328325d861
71. Keidar S, Gamliel-Lazarovich A, Kaplan M, Pavlotzky E, Hamoud S, Hayek T, et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ Res. (2005) 97:946–53. doi: 10.1161/01.RES.0000187500.24964.7A
72. Te Riet L, van Esch JH, Roks AJ, van den Meiracker AH, Danser AH. Hypertension: renin-angiotensin-aldosterone system alterations. Circ Res. (2015) 116:960–75. doi: 10.1161/CIRCRESAHA.116.303587
73. Hamming I, Cooper ME, Haagmans BL, Hooper NM, Korstanje R, Osterhaus AD, et al. The emerging role of ACE2 in physiology and disease. J Pathol. (2007) 212:1–11. doi: 10.1002/path.2162
74. Patel S, Rauf A, Khan H, Abu-Izneid T. Renin-angiotensin-aldosterone (RAAS): the ubiquitous system for homeostasis and pathologies. Biomed Pharmacother. (2017) 94:317–25. doi: 10.1016/j.biopha.2017.07.091
75. Sert M, Tetiker T, Kirim S. Comparison of the efficiency of anti-androgenic regimens consisting of spironolactone, Diane 35, and cyproterone acetate in hirsutism. Acta Med Okayama. (2003) 57:73–6. doi: 10.18926/AMO/32820
76. Steelman SL, Brooks JR, Morgan ER, Patanelli DJ. Anti-androgenic activity of spironolactone. Steroids. (1969) 14:449–50. doi: 10.1016/S0039-128X(69)80007-3
77. Broulik PD, Stárka L. Antiandrogenic and antirenotropic effect of spironolactone. Endokrinologie. (1976) 68:35–9.
78. Vecchiola A, Fuentes CA, Solar I, Lagos CF, Opazo MC, Muñoz-Durango N, et al. Eplerenone implantation improved adipose dysfunction averting RAAS activation and cell division. Front Endocrinol. (2020) 11:223. doi: 10.3389/fendo.2020.00223
79. Feraco A, Armani A, Mammi C, Fabbri A, Rosano GM, Caprio M. Role of mineralocorticoid receptor and renin-angiotensin-aldosterone system in adipocyte dysfunction and obesity. J Steroid Biochem Mol Biol. (2013) 137:99–106. doi: 10.1016/j.jsbmb.2013.02.012
80. Ji WJ, Ma YQ, Zhang X, Zhang L, Zhang YD, Su CC, et al. Inflammatory monocyte/macrophage modulation by liposome-entrapped spironolactone ameliorates acute lung injury in mice. Nanomedicine. (2016) 11:1393–406. doi: 10.2217/nnm-2016-0006
81. Ji WJ, Ma YQ, Zhou X, Zhang YD, Lu RY, Guo ZZ, et al. Spironolactone attenuates bleomycin-induced pulmonary injury partially via modulating mononuclear phagocyte phenotype switching in circulating and alveolar compartments. PLoS ONE. (2013) 8:e81090. doi: 10.1371/journal.pone.0081090
82. Rafatian N, Westcott KV, White RA, Leenen FH. Cardiac macrophages and apoptosis after myocardial infarction: effects of central MR blockade. Am J Physiol Regul Integr Comp Physiol. (2014) 307:R879–87. doi: 10.1152/ajpregu.00075.2014
83. Zhang L, Hao JB, Ren LS, Ding JL, Hao LR. The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis. Lab Invest. (2014) 94:839–50. doi: 10.1038/labinvest.2014.69
84. Ozacmak HS, Ozacmak VH, Barut F, Arasli M, Ucan BH. Pretreatment with mineralocorticoid receptor blocker reduces intestinal injury induced by ischemia and reperfusion: involvement of inhibition of inflammatory response, oxidative stress, nuclear factor κB, and inducible nitric oxide synthase. J Surg Res. (2014) 191:350–61. doi: 10.1016/j.jss.2014.04.040
85. Kato Y, Kamiya H, Koide N, Odkhuu E, Komatsu T, Dagvadorj J, et al. Spironolactone inhibits production of proinflammatory mediators in response to lipopolysaccharide via inactivation of nuclear factor-κB. Immunopharmacol Immunotoxicol. (2014) 36:237–41. doi: 10.3109/08923973.2014.921690
86. Lieber GB, Fernandez X, Mingo GG, Jia Y, Caniga M, Gil MA, et al. Mineralocorticoid receptor antagonists attenuate pulmonary inflammation and bleomycin-evoked fibrosis in rodent models. Eur J Pharmacol. (2013) 718:290–8. doi: 10.1016/j.ejphar.2013.08.019
87. Fraccarollo D, Galuppo P, Schraut S, Kneitz S, van Rooijen N, Ertl G, et al. Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response. Hypertension. (2008) 51:905–14. doi: 10.1161/HYPERTENSIONAHA.107.100941
88. Lacombe B, Morel M, Margottin-Goguet F, Ramirez BC. Specific inhibition of HIV infection by the action of spironolactone in T cells. J Virol. (2016) 90:10972–80. doi: 10.1128/JVI.01722-16
89. Verma D, Thompson J, Swaminathan S. Spironolactone blocks Epstein-Barr virus production by inhibiting EBV SM protein function. Proc Natl Acad Sci USA. (2016) 113:3609–14. doi: 10.1073/pnas.1523686113
90. Yartaş Dumanli G, Dilken O, Ürkmez S. Use of spironolactone in SARS-CoV-2 ARDS patients. Turk J Anaesthesiol Reanim. (2020) 48:254–55. doi: 10.5152/TJAR.2020.569
Keywords: COVID-19, SARS-CoV-2, coronavirus, pandemic, spironolactone, ARDS (acute respiratory distress syndrome), androgen receptor antagonist, TMPRSS2
Citation: Cadegiani FA, Wambier CG and Goren A (2020) Spironolactone: An Anti-androgenic and Anti-hypertensive Drug That May Provide Protection Against the Novel Coronavirus (SARS-CoV-2) Induced Acute Respiratory Distress Syndrome (ARDS) in COVID-19. Front. Med. 7:453. doi: 10.3389/fmed.2020.00453
Received: 20 April 2020; Accepted: 08 July 2020;
Published: 28 July 2020.
Edited by:
Ata Murat Kaynar, University of Pittsburgh School of Medicine, United StatesReviewed by:
Torsten Gerriet Blum, Helios Kliniken, GermanyCopyright © 2020 Cadegiani, Wambier and Goren. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Flavio A. Cadegiani, flavio.cadegiani@unifesp.br; f.cadegiani@gmail.com