The spike protein of SARS-CoV-2 induces heme oxygenase-1: Pathophysiologic implications

Raman Deep Singh, Michael A. Barry, Anthony J. Croatt, Allan W. Ackerman, Joseph P. Grande, Rosa M. Diaz, Richard G. Vile, Anupam Agarwal, Karl A. Nath

Research output: Contribution to journalArticlepeer-review


Background: Acute kidney injury (AKI) is both a consequence and determinant of outcomes in COVID-19. The kidney is one of the major organs infected by the causative virus, SARS-CoV-2. Viral entry into cells requires the viral spike protein, and both the virus and its spike protein appear in the urine of COVID-19 patients with AKI. We examined the effects of transfecting the viral spike protein of SARS-CoV-2 in kidney cell lines. Methods: HEK293, HEK293-ACE2+ (stably overexpressing ACE2), and Vero E6 cells having endogenous ACE2 were transfected with SARS-CoV-2 spike or control plasmid. Assessment of gene and protein expression, and syncytia formation was performed, and the effects of quercetin on syncytia formation examined. Findings: Spike transfection in HEK293-ACE2+ cells caused syncytia formation, cellular sloughing, and focal denudation of the cell monolayer; transfection in Vero E6 cells also caused syncytia formation. Spike expression upregulated potentially nephrotoxic genes (TNF-α, MCP-1, and ICAM1). Spike upregulated the cytoprotective gene HO-1 and relevant signaling pathways (p-Akt, p-STAT3, and p-p38). Quercetin, an HO-1 inducer, reduced syncytia formation and spike protein expression. Interpretation: The major conclusions of the study are: 1) Spike protein expression in kidney cells provides a relevant model for the study of maladaptive and adaptive responses germane to AKI in COVID-19; 2) such spike protein expression upregulates HO-1; and 3) quercetin, an HO-1 inducer, may provide a clinically relevant/feasible protective strategy in AKI occurring in the setting of COVID-19. Funding: R01-DK119167 (KAN), R01-AI100911 (JPG), P30-DK079337; R01-DK059600 (AA).

Original languageEnglish (US)
Article number166322
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number3
StatePublished - Mar 1 2022


  • Acute kidney injury
  • Angiotensin-converting enzyme 2
  • COVID-19
  • Heme oxygenase-1
  • SARS-CoV-2
  • Spike protein
  • Syncytia

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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