The role of renin-angiotensin system and angiotensin-converting enzyme 2 (ACE2) in the development and course of viral infection COVID-19 in patients with diabetes mellitus

The role of renin-angiotensin system (RAS) in general and angiotensin-converting enzyme 2 (ACE2) in particular in the  pathogenesis and course of viral infection caused by SARS-CoV-2 (COVID-19) is of particular interest. This is due not only to the fact that ACE2 is a receptor for the virus the target cells. RAS hyperactivation in patients with arterial hypertension, cardiovascular disease and diabetes mellitus, is considered one of the most important factors for a more severe infection in persons with concomitant pathology. In addition, the effects of PAS blockage with angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARBs) remains one of the most discussed topics in the literature on COVID-19. This review presents the data on the interaction between the virus and the main components of RAS and the factors influencing their expression level, the impact of ACE ­inhibitors and ARBs therapy on the disease outcome, and presents the perspectives of the treatment with recombinant ACE 2.

1. Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708−1720. doi: https://doi.org/10.1056/NEJMoa2002032

2. Wu Z, McGoogan JM. 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: https://doi.org/10.1001/jama.2020.2648

3. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8(5):475–481. doi: https://doi.org/10.1016/S2213-2600(20)30079-5

4. Wu C, Chen X, Cai Y, 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(7):1–11. doi: https://doi.org/10.1001/jamainternmed.2020.0994

5. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis. Int J Infect Dis. 2020;94:91–95. doi: https://doi.org/10.1016/j.ijid.2020.03.017

6. Bode B, Garrett V, Messler J, et al. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. J Diabetes Sci Technol. 2020;14(4):813–821. doi: https://doi.org/10.1177/1932296820924469

7. Zhu L, She ZG, Cheng X, et al. Association of blood glucose control and outcomes in patients with COVID-19 and Pre-existing Type 2 diabetes. Cell Metab. 2020;31(6):1068–1077.e3. doi: https://doi.org/10.1016/j.cmet.2020.04.021

8. Jafar N, Edriss H, Nugent K. The effect of short-term hyperglycemia on the innate immune system. Am J Med Sci. 2016;351(2):201–211. doi: https://doi.org/10.1016/j.amjms.2015.11.011

9. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999;26(3-4):259–265. doi: https://doi.org/10.1111/j.1574-695X.1999.tb01397.x

10. Ji HL, Zhao R, Matalon S, Matthay MA. Elevated Plasmin(ogen) as a common risk factor for COVID-19 susceptibility. Physiol Rev. 2020;100(3):1065–1075. doi: https://doi.org/10.1152/physrev.00013.2020

11. Fernandez C, Rysä J, Almgren P, et al. Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality. J Intern Med. 2018;284(4):377–387. doi: https://doi.org/10.1111/joim.12783

12. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181(2):271–280.е8. doi: https://doi.org/10.1016/j.cell.2020.02.052

13. Glowacka I, Bertram S, Müller MA, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85(9):4122–4134. doi: https://doi.org/10.1128/JVI.02232-10

14. Peci S, Inzirillo F, Peci F. The role of soluble recombinant ACE2 in SARS-COV-2 patients. EC Pulmonology and Respiratory Medicine. 2020;9(7):17–22.

15. Xiao L, Sakagami H, Miwa N. ACE2: The key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: demon or angel? Viruses. 2020;12(5):491. doi: https://doi.org/10.3390/v12050491

16. South AM, Tomlinson L, Edmonston D, et al. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020;16(6):305–307. doi: https://doi.org/10.1038/s41581-020-0279-4

17. Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J. 2013;77(2):301–308. doi: https://doi.org/10.1253/circj.cj-12-1544

18. Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/Angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118(8):1313–1326. doi: https://doi.org/10.1161/CIRCRESAHA.116.307708

19. Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci. 2004;25(6):291–294. doi: https://doi.org/10.1016/j.tips.2004.04.001

20. Zhang H, Penninger JM, Li Y, et al. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020;46(4):586–590. doi: https://doi.org/10.1007/s00134-020-05985-9

21. Benigni A, Cassis P, Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med. 2010;2(7):247–257. doi: https://doi.org/10.1002/emmm.201000080

22. Mateo T, Abu Nabah YN, Abu Taha M, et al. Angiotensin II-induced mononuclear leukocyte interactions with arteriolar and venular endothelium are mediated by the release of different CC chemokines. J Immunol. 2006;176(9):5577–5586. doi: https://doi.org/10.4049/jimmunol.176.9.5577

23. Montezano AC, Cat AN, Rios FJ, Touyz RM. Angiotensin II and vascular injury. Curr Hypertens Rep. 2014;16(6):431. doi: https://doi.org/10.1007/s11906-014-0431-2

24. McGonagle D, O’Donnell J, Sharif K, et al. Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia. Lancet Rheumatol. 2020;2(7):e437–e445. https://doi.org/10.1016/s2665-9913(20)30121-1

25. Yamamoto S, Yancey PG, Zuo Y, et al. Macrophage polarization by angiotensin II-type 1 receptor aggravates renal injury-acceleration of atherosclerosis. Arterioscler Thromb Vasc Biol. 2011;31(12):2856–2864. doi: https://doi.org/10.1161/ATVBAHA.111.237198

26. Lee YB, Nagai A, Kim SU. Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res. 2002;69(1):94–103. doi: https://doi.org/10.1002/jnr.10253

27. Magalhães GS, Rodrigues-Machado MG, Motta-Santos D, et al. Angiotensin-(1-7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation. Br J Pharmacol. 2015;172(9):2330–2342. doi: https://doi.org/10.1111/bph.13057

28. Li Y, Cao Y, Zeng Z, et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis prevents lipopolysaccharide-induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF-κB pathways. Sci Rep. 2015;5:8209. doi: https://doi.org/10.1038/srep08209

29. Meng Y, Yu CH, Li W, et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis protects against lung fibrosis by inhibiting the MAPK/NF-κB pathway. Am J Respir Cell Mol Biol. 2014;50(4):723–736. doi: https://doi.org/10.1165/rcmb.2012-0451OC

30. Pai WY, Lo WY, Hsu T, et al. Angiotensin-(1-7) inhibits thrombin-induced endothelial phenotypic changes and reactive oxygen species production via NADPH Oxidase 5 downregulation. Front Physiol. 2017;8:994. doi: https://doi.org/10.3389/fphys.2017.00994

31. Santos RA, Sampaio WO, Alzamora AC, et al. The ACE2/Angiotensin-(1-7)/MAS Axis of the renin-angiotensin system: focus on Angiotensin-(1-7). Physiol Rev. 2018;98(1):505–553. doi: https://doi.org/10.1152/physrev.00023.2016

32. Yuan L, Li Y, Li G, et al. Ang(1-7) treatment attenuates β-cell dysfunction by improving pancreatic microcirculation in a rat model of Type 2 diabetes. J Endocrinol Invest. 2013;36(11):931–937. doi: https://doi.org/10.3275/8951

33. Dijkman R, Jebbink MF, Deijs M, et al. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. J Gen Virol. 2012;93(Pt 9):1924–1929. doi: https://doi.org/10.1099/vir.0.043919-0

34. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clinical Science. 2020;134(5):543–545. doi: https://doi.org/10.1042/CS20200163

35. Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631–637. doi: https://doi.org/10.1002/path.1570

36. Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 2020;12(1):8. doi: https://doi.org/10.1038/s41368-020-0074-x

37. Bunyavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA. 2020;323(23):2427–2429. doi: https://doi.org/10.1001/jama.2020.8707

38. Xie X, Chen J, Wang X, et al. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006;78(19):2166–2171. doi: https://doi.org/10.1016/j.lfs.2005.09.038

39. Sun P, Lu X, Xu C, et al. Understanding of COVID-19 based on current evidence. J Med Virol. 2020;92(6):548–551. doi: https://doi.org/10.1002/jmv.25722

40. Pal R, Bhansali A. COVID-19, diabetes mellitus and ACE2: The conundrum. Diabetes Res Clin Pract. 2020;162:108132. doi: https://doi.org/10.1016/j.diabres.2020.108132

41. Tikellis C, Bernardi S, Burns WC. Angiotensin-converting enzyme 2 is a key modulator of the renin-angiotensin system in cardiovascular and renal disease. Curr Opin Nephrol Hypertens. 2011;20(1):62–68. doi: https://doi.org/10.1097/MNH.0b013e328341164a

42. Devaux CA, Rolain JM, Raoult D. ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J Microbiol Immunol Infect. 2020;53(3):425–435. doi: https://doi.org/10.1016/j.jmii.2020.04.015

43. Rice GI, Jones AL, Grant PJ, et al. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension. 2006;48(5):914–920. doi: https://doi.org/10.1161/01.HYP.0000244543.91937.79

44. Asselta R, Paraboschi EM, Mantovani A, Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. medRxiv. 2020;03.30.20047878. doi: https://doi.org/10.1101/2020.03.30.20047878

45. Chaoxin J, Daili S, Yanxin H, et al. The influence of angiotensin-converting enzyme 2 gene polymorphisms on type 2 diabetes mellitus and coronary heart disease. Eur Rev Med Pharmacol Sci. 2013;17(19):2654–2659.

46. Yang M, Zhao J, Xing L, Shi L. The association between angiotensin-converting enzyme 2 polymorphisms and essential hypertension risk: A meta-analysis involving 14,122 patients. J Renin Angiotensin Aldosterone Syst. 2015;16(4):1240–1244. doi: https://doi.org/10.1177/1470320314549221

47. Wu YH, Li JY, Wang C, et al. The ACE2 G8790A polymorphism: involvement in Type 2 diabetes mellitus combined with cerebral stroke. J Clin Lab Anal. 2017;31(2):e22033. doi: https://doi.org/10.1002/jcla.22033

48. 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(4):e21. doi: https://doi.org/10.1016/S2213-2600(20)30116-8

49. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020;27(3):taaa041. doi: https://doi.org/10.1093/jtm/taaa041

50. Kuster GM, Pfister O, Burkard T, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020;41(19):1801–1803. doi: https://doi.org/10.1093/eurheartj/ehaa235

51. Zheng Y, Ma Y, Zhang J, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259–260. https://doi.org/10.1038/s41569-020-0360-5

52. Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45–51. doi: https://doi.org/10.1042/BJ20040634

53. Milne S, Yang CX, Timens W, et al. SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors. Lancet Respir Med. 2020;8(6):e50–e51. doi: https://doi.org/10.1016/S2213-2600(20)30224-1

54. Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J. 2020;41(19):1810–1817. doi: https://doi.org/10.1093/eurheartj/ehaa373.

55. de Abajo FJ, Rodríguez-Martín S, Lerma V, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet. 2020;395(10238):1705–1714. doi: https://doi.org/10.1016/S0140-6736(20)31030-8

56. Шестакова М.В., Викулова О.К., Исаков М.А., Дедов И.И. Сахарный диабет и COVID-19: анализ клинических исходов по данным регистра сахарного диабета Российской Федерации // Проблемы эндокринологии. — 2020. — Т. 66. — №1. — С. 112–123. [Shestakova MV. Diabetes and COVID-19: analysis of the clinical outcomes according to the data of the Russian diabetes registry. Problemy endocrinologii. 2020;66(1):112–123. (In Russ.)]. doi: https://doi.org/10.14341/probl12458

57. Zhang P, Zhu L, Cai J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020;126(12):1671–1681. doi: https://doi.org/10.1161/CIRCRESAHA.120.317134

58. Bean D, Kraljevic Z, Searle T, et al. ACE-inhibitors and Angiotensin-2 Receptor Blockers are not associated with severe SARS- COVID19 infection in a multi-site UK acute Hospital Trust. medRxiv. 2020. doi: https://doi.org/10.1101/2020.04.07.20056788

59. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020;10.1002/ddr.21656. doi: https://doi.org/10.1002/ddr.21656

60. Verdecchia P, Angeli F, Reboldi G. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and coronavirus. J Hypertens. 2020;38(6):1190–1191. doi: https://doi.org/10.1097/HJH.0000000000002469

61. Peiró C, Moncada S. Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARS-CoV-2 Infection? Circulation. 2020;141(21):1665–1666. doi: https://doi.org/10.1161/CIRCULATIONAHA.120.047297