Acta Scientific Otolaryngology (ASOL) (ISSN: 2582-5550)

Review Article Volume 2 Issue 12

Nrf2-ACE2R Pathway to Halt the Entrance of SARS-CoV-2 in Human: A New Strategy in Targeted Therapy

Muhammad Torequl Islam*

Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh

*Corresponding Author: Muhammad Torequl Islam, Department of Pharmacy, Life Science Faculty, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj-8100, Bangladesh.

Received: September 09, 2020; Published: November 25, 2020



  The nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulates many important genes that encode of our body antioxidant systems and display diverse and important physiological functions. Loss of Nrf2 is associated with an upregulated expression of angiotensin converting enzyme 2 receptor (ACE2R) in experimental animals. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) use ACE2R for the entry in human lung epithelial and enteric cells through binding with its spike glycoprotein (S). ACE2 upregulation is associated with many diseases, including liver injury, inflammation and insulin resistance, myocardial dysfunction, acute decompensated heart failure, and type 2 diabetes. However, deletion or loss of its activity is associated with atherosclerotic renal injury and kidney diseases, heart failure, and pulmonary arterial hypertension. Therefore, targeting Nrf2 alone or Nrf2-ACE2 modulators might be helpful to manage these types of patients with SARS-CoV-2 infection. Adequate pre-clinical and clinical research is necessary to establish this concepts.

Keywords: ACE2; Nrf2; SARS-CoV-2; Covid-19



  1. Tebay LE., et al. “Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease”. Free Radical Biology and Medicine 88 (2015): 108-146.
  2. Panieri E and Saso L. “Potential Applications of NRF2 Inhibitors in Cancer Therapy”. Oxidative Medicine and Cellular Longevity 2019 (2019): 8592348.
  3. Kannan S., et al. “Nrf2 deficiency prevents reductive stress-induced hypertrophic cardiomyopathy”. Cardiovascular Research1 (2013): 63-73.
  4. Bauer AK., et al. “Targeted Deletion of Nrf2 Reduces Urethane-Induced Lung Tumor Development in Mice”. PLoS One10 (2011): e26590.
  5. Matzinger M., et al. “Activation of Nrf2 signaling by natural products-can it alleviate diabetes?” Biotechnology Advances6 (2018): 1738-1767.
  6. Tarantini S., et al. “Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood–Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype”. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 7 (2018): 853-863.
  7. Rojo AI., et al. “NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology”. Redox Biology 13 (2017): 444-451.
  8. Zhang C., et al. “ACE2‐EPC‐EXs protect ageing ECs against hypoxia/reoxygenation‐induced injury through the miR‐18a/Nox2/ROS pathway”. Journal of Cellular and Molecular Medicine3 (2018): 1873-1882.
  9. Knipe DM and Howley PM. “Fields' Virology”. vol 1. 5th ed. Wolters Kluwer (2007).
  10. Kannan S., et al. “COVID-19 (Novel Coronavirus 2019) –recent trends”. European Review for Medical and Pharmacological Sciences 24 (2020): 2006-2011.
  11. Gu J and Korteweg C. “Pathology and pathogenesis of severe acute respiratory syndrome”. American Journal of Pathology 170 (2007): 1136-1147.
  12. Kuster GM., et al. “SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19?” European Heart Journal (2020): ehaa235.
  13. Peña Silva RA., et al. “Impact of ACE2 deficiency and oxidative stress on cerebrovascular function with aging”. Stroke 12 (2012): 3358-3363.
  14. Jiang F., et al. “Angiotensin-converting enzyme 2 and angiotensin 1–7: novel therapeutic targets”. Nature Reviews Cardiology 7 (2014): 413-426.
  15. Zhao S., et al. “Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice”. Endocrinology2 (2018): 836-852.
  16. Takeshita H., et al. “Angiotensin‐converting enzyme 2 deficiency accelerates and angiotensin 1‐7 restores age‐related muscle weakness in mice”. Journal of Cachexia Sarcopenia Muscle 5 (2018): 975-986.
  17. Gupte M., et al. “Angiotensin Converting Enzyme 2 Contributes to Sex Differences in the Development of Obesity Hypertension in C57BL/6 Mice”. Arteriosclerosis, Thrombosis, and Vascular Biology 6 (2012): 1392-1399.
  18. Giani JF., et al. “Upregulation of the Angiotensin-Converting Enzyme 2/Angiotensin- (1-7)/Mas Receptor Axis in the Heart and the Kidney of Growth Hormone Receptor knock-out Mice”. Growth Hormone IGF Research 6 (2012): 224-233.
  19. Oarhe CI., et al. “Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts”. Pediatric Research5 (2015): 656-662.
  20. Sunde GA., et al. “Hypoxia and hypotension in patients intubated by physician staffed helicopter emergency medical services - a prospective observational multi-centre study”. BMC Emergency Medicine 17 (2017): 22.
  21. Soendergaard C., et al. “Growth Hormone Resistance—Special Focus on Inflammatory Bowel Disease”. International Journal of Molecular Sciences 5 (2017): 1019.
  22. Lin C-I., et al. “Instillation of particulate matter 2.5 induced acute lung injury and attenuated the injury recovery in ACE2 knockout mice”. International Journal of Biological Sciences 3 (2018): 253-265.
  23. Tkach M., et al. “p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth”. Endocrine-Related Cancer2 (2013): 197-212.
  24. Levy DE and Loomis CA. “STAT3 signaling and the hyper-IgE syndrome”. The New England Journal of Medicine 16 (2007): 1655-1658.
  25. Fung TS., et al. “Coronavirus-induced ER stress response and its involvement in regulation of coronavirus–host interactions”. Virus Research 194 (2014): 110-123.
  26. Gkouveris I., et al. “Erk1/2 activation and modulation of STAT3 signaling in oral cancer”. Oncology Report (2014): 2175-2182.
  27. Tao L., et al. “Angiotensin-converting enzyme 2 activator diminazene aceturate prevents lipopolysaccharide-induced inflammation by inhibiting MAPK and NF-κB pathways in human retinal pigment epithelium”. Journal of Neuroinflammation 13 (2016): 35.
  28. Dodson M., et al. “Modulating NRF2 in disease: Timing is everything”. Annual Review of Pharmacology and Toxicology 59 (2019): 555-575.
  29. Huentelman MJ., et al. “Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor”. Hypertension 44 (2004): 903-906.
  30. Han DP., et al. “Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor”. Virology 350 (2006): 15-25.
  31. Ho T-Y., et al. “Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction”. Antiviral Research2 (2007): 92-101.
  32. Kesic MJ., et al. “Nrf2 Expression Modifies Influenza A Entry and Replication in Nasal Epithelial Cells”. Free Radical Biology and Medicine2 (2011): 444-453.
  33. Zhang R., et al. “COVID-19: Melatonin as a potential adjuvant treatment”. Life Science 250 (2020): 117583.
  34. Fang J., et al. “Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress”. Aging (Albany NY)10 (2018): 2954-2972.
  35. Poppe M., et al. “The NF-κB-dependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells”. PLoS Pathogen3 (2017): e1006286.
  36. Zhang Z-Z., et al. “Cardiac protective effects of irbesartan via the PPAR-gamma signaling pathway in angiotensin-converting enzyme 2-deficient mice”. Journal of Translational Medicine 11 (2013): 229.
  37. Paizis G., et al. “Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2”. Gut12 (2005): 1790-1796.
  38. Herath CB., et al. “Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin- (1–7) levels in experimental biliary fibrosis”. Journal of Hepatology3 (2007): 387-395.
  39. Zhong J-C., et al. “Enhanced angiotensin converting enzyme 2 regulates the insulin/Akt signalling pathway by blockade of macrophage migration inhibitory factor expression”. British Journal of Pharmacology1 (2008): 66-74.
  40. Epelman S., et al. “Soluble Angiotensin Converting Enzyme 2 in Human Heart Failure: Relation with Myocardial Function and Clinical Outcomes”. Journal of Cardiac Failure7 (2009): 565-571.
  41. Shao Z., et al. “Increasing Serum Soluble Angiotensin Converting Enzyme 2 Activity following Intensive Medical Therapy is Associated with Better Prognosis in Acute Decompensated Heart Failure”. Journal of Cardiac Failure9 (2013): 605-610.
  42. Zhang Y., et al. “Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes”. Antioxidant Redox Signal11 (2015): 880-892.
  43. Gutta S., et al. “Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes”. American Journal of Physiology-Renal Physiology2 (2018): F263-F274.
  44. Jin H-Y., et al. “Deletion of angiotensin-converting enzyme 2 exacerbates renal inflammation and injury in apolipoprotein E-deficient mice through modulation of the nephrin and TNF-alpha-TNFRSF1A signaling”. Journal of Translational Medicine 13 (2015): 255.
  45. Patel VB., et al. “Role of the ACE2/Angiotensin 1–7 axis of the Renin-Angiotensin System in Heart Failure”. Circulation Research8 (2016): 1313-1326.
  46. Hemnes AR., et al. “A potential therapeutic role for Angiotensin Converting Enzyme 2 in human pulmonary arterial hypertension”. European Respiratory Journal6 (2018): 1702638.
  47. Hassan SM., et al. “The Nrf2 Activator (DMF) and Covid-19: Is there a Possible Role?” Medical Archives 2 (2020):134-138.
  48. Cuadrado A., et al. “Can Activation of NRF2 Be a Strategy against COVID-19?” Trends in Pharmacological Sciences 9 (2020): 598-610.


Citation: Muhammad Torequl Islam. “Nrf2-ACE2R Pathway to Halt the Entrance of SARS-CoV-2 in Human: A New Strategy in Targeted Therapy". Acta Scientific Otolaryngology 2.12 (2020): 32-37.


Acceptance rate34%
Acceptance to publication20-30 days

Indexed In

News and Events

  • Certification for Review
    Acta Scientific certifies the Editors/reviewers for their review done towards the assigned articles of the respective journals.
  • Submission Timeline for Upcoming Issue
    The last date for submission of articles for regular Issues is September 30, 2021.
  • Publication Certificate
    Authors will be issued a "Publication Certificate" as a mark of appreciation for publishing their work.
  • Best Article of the Issue
    The Editors will elect one Best Article after each issue release. The authors of this article will be provided with a certificate of “Best Article of the Issue”.
  • Welcoming Article Submission
    Acta Scientific delightfully welcomes active researchers for submission of articles towards the upcoming issue of respective journals.
  • Contact US