Renin Angiotensin System and Bradykinin pathways in COVID-19 (Homo sapiens)

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Description

This pathway describes imbalances in RAS and Bradykinin pathways in COVID-19.

The expression of several genes in these pathways is affected in by SARS-CoV-2:

  • SERPING1 is downregulated, which cancels the suppression of F12 of the intrinsic coagulation cascade, resulting in the production of bradykinin from kallikrein and KNG.
  • ACE is downregulated, which increases bradykinin levels.
  • ACE2 is upregulated, ACE is downregulated, which causes an increase in Angiotensin 1-9 and sensitization of bradykinin receptors.
  • NFkappaB is suppressed by SARS-Cov-2, decreasing its binding to the ACE promoter and subsequent transcription.

The result of a hyperactive bradykinin system is vasodilation to the point of vascular leakage and infiltration of inflammatory cells.

The pathway is based on Figure 2A from [Garvin et al.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410499/).

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Bibliography

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  1. de Maat S, de Mast Q, Danser AHJ, van de Veerdonk FL, Maas C; ''Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection.''; Semin Thromb Hemost, 2020 PubMed Europe PMC Scholia
  2. Li P, Kondo T, Numaguchi Y, Kobayashi K, Aoki M, Inoue N, Okumura K, Murohara T; ''Role of bradykinin, nitric oxide, and angiotensin II type 2 receptor in imidapril-induced angiogenesis.''; Hypertension, 2008 PubMed Europe PMC Scholia
  3. Maron BA, Leopold JA; ''Mineralocorticoid receptor antagonists and endothelial function.''; Curr Opin Investig Drugs, 2008 PubMed Europe PMC Scholia
  4. Bassett MH, White PC, Rainey WE; ''The regulation of aldosterone synthase expression.''; Mol Cell Endocrinol, 2004 PubMed Europe PMC Scholia
  5. de Maat S, de Mast Q, Danser AHJ, van de Veerdonk FL, Maas C; ''Impaired Breakdown of Bradykinin and Its Metabolites as a Possible Cause for Pulmonary Edema in COVID-19 Infection.''; Semin Thromb Hemost, 2020 PubMed Europe PMC Scholia
  6. Li P, Kondo T, Numaguchi Y, Kobayashi K, Aoki M, Inoue N, Okumura K, Murohara T; ''Role of bradykinin, nitric oxide, and angiotensin II type 2 receptor in imidapril-induced angiogenesis.''; Hypertension, 2008 PubMed Europe PMC Scholia
  7. Alessi D, MacDougall LK, Sola MM, Ikebe M, Cohen P; ''The control of protein phosphatase-1 by targetting subunits. The major myosin phosphatase in avian smooth muscle is a novel form of protein phosphatase-1.''; Eur J Biochem, 1992 PubMed Europe PMC Scholia
  8. Batenburg WW, Jan Danser AH; ''The (pro)renin receptor: a new addition to the renin-angiotensin system?''; Eur J Pharmacol, 2008 PubMed Europe PMC Scholia
  9. Ferreira AJ, Raizada MK; ''Are we poised to target ACE2 for the next generation of antihypertensives?''; J Mol Med, 2008 PubMed Europe PMC Scholia
  10. Vianna RM, Calixto JB; ''Characterization of the receptor and the mechanisms underlying the inflammatory response induced by des-Arg9-BK in mouse pleurisy.''; Br J Pharmacol, 1998 PubMed Europe PMC Scholia
  11. Garvin MR, Alvarez C, Miller JI, Prates ET, Walker AM, Amos BK, Mast AE, Justice A, Aronow B, Jacobson D; ''A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm''; eLife, 2020
  12. D'Alonzo D, De Fenza M, Pavone V; ''COVID-19 and pneumonia: a role for the uPA/uPAR system.''; Drug Discov Today, 2020 PubMed Europe PMC Scholia
  13. Weir MR; ''Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?''; Clin Ther, 2007 PubMed Europe PMC Scholia
  14. Carvalho PR, Sirois P, Fernandes PD; ''The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection.''; Peptides, 2020 PubMed Europe PMC Scholia
  15. Schwartz GL, Turner ST; ''Pharmacogenetics of antihypertensive drug responses.''; Am J Pharmacogenomics, 2004 PubMed Europe PMC Scholia
  16. Denninger JW, Marletta MA; ''Guanylate cyclase and the .NO/cGMP signaling pathway.''; Biochim Biophys Acta, 1999 PubMed Europe PMC Scholia
  17. ''Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19''; Viruses, 2020 PubMed Europe PMC Scholia
  18. Vianna RM, Calixto JB; ''Characterization of the receptor and the mechanisms underlying the inflammatory response induced by des-Arg9-BK in mouse pleurisy.''; Br J Pharmacol, 1998 PubMed Europe PMC Scholia
  19. Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, Noble NA, Border W; ''Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms.''; Kidney Int, 2006 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
142202view19:12, 15 December 2025KhanspersModified description
142201view19:11, 15 December 2025Khanspersupdated title
140128view12:34, 31 July 2025EgonwCalcium ion with unicode
137796view06:27, 8 March 2025EgonwModified description
129170view14:36, 14 March 2024DeSlUpdated description
125829view20:41, 12 March 2023EgonwAdded missing reference info
125781view09:46, 10 March 2023DeSlChanged 'MIM-binding' between two metaboliutes to 'MIM-conversion'
120081view21:42, 29 October 2021Khansperscleaning up lit refs
120080view21:40, 29 October 2021Khansperscleaning up lit refs
120079view21:37, 29 October 2021Khanspersupdated lit refs
118979view06:49, 6 June 2021EgonwTranslocation
118837view09:14, 2 June 2021EweitzOntology Term : 'COVID-19' added !
118836view09:14, 2 June 2021EweitzOntology Term : 'DOID:934' removed !
118835view09:14, 2 June 2021EweitzOntology Term : 'DOID:2945' removed !
118834view09:13, 2 June 2021EweitzOntology Term : 'vascular associated smooth muscle cell' added !
116369view12:43, 4 May 2021EweitzModified title
115143view18:14, 28 January 2021KhanspersModified description
115142view18:13, 28 January 2021Khanspersfixed unconnected
114342view15:12, 8 January 2021PennyUpdated link from Angiotensin II to AGTR1 and SERPINE1 leading to the Complement and Coagulation Cascades-pathway.
114074view06:14, 21 December 2020EgonwMade two process label pathway DataNodes
114025view15:26, 17 December 2020EgonwReplaced the ChEBI ID of the protonated form with the ID for the neutral compound.
113957view13:52, 11 December 2020EgonwNew pathway also clickable
113929view13:56, 10 December 2020PennyAdded link to Complement and Coagulation cascades WP558
113912view21:25, 8 December 2020KhanspersModified description
113911view21:09, 8 December 2020KhanspersModified description
113910view21:05, 8 December 2020KhanspersUpdate literature reference
113909view20:47, 8 December 2020KhanspersModified description
113907view19:49, 8 December 2020KhanspersModified description
113906view19:34, 8 December 2020Khanspersupdated layout
113841view17:47, 30 November 2020Marvin M2Added bits downstream of bradykinin receptors
113829view08:29, 30 November 2020FehrhartOntology Term : 'disease pathway' added !
113828view08:29, 30 November 2020FehrhartOntology Term : 'viral infectious disease' added !
113827view08:29, 30 November 2020FehrhartOntology Term : 'severe acute respiratory syndrome' added !
113826view08:28, 30 November 2020Fehrhartsmall graphical adaptions
113635view05:33, 9 November 2020EgonwModified title
111967view22:48, 11 September 2020KhanspersNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
20-HETEMetaboliteCHEBI:34306 (ChEBI)
ACEGeneProduct1636 (Entrez Gene)
ACE2GeneProduct59272 (Entrez Gene)
ACE2GeneProductENSG00000130234 (Ensembl)
AGTGeneProduct183 (Entrez Gene)
AGTR1GeneProduct185 (Entrez Gene)
AGTR2GeneProduct186 (Entrez Gene)
AldosteroneMetabolite52-39-1 (CAS)
Ang 1-7Metabolite110354 (Chemspider)
Ang 1-9MetaboliteC15851 (KEGG Compound)
Angiotensin IMetabolite3081372 (PubChem-compound)
Angiotensin IIMetaboliteHMDB0001035 (HMDB)
Arachidonic acidMetaboliteCHEBI:15843 (ChEBI)
BDKRB1GeneProduct623 (Entrez Gene)
BDKRB2GeneProduct624 (Entrez Gene)
BradykininMetaboliteHMDB0004246 (HMDB)
CPN1GeneProductENSG00000120054 (Ensembl)
CYP24A1GeneProductENSG00000019186 (Ensembl)
CYP3A4GeneProductENSG00000160868 (Ensembl)
Ca²⁺MetaboliteHMDB0000464 (HMDB)
Complement and Coagulation CascadesPathwayWP558 (WikiPathways)
Cyclic guanosine monophosphateMetaboliteCHEBI:16356 (ChEBI)
DegradationPathway
F12GeneProductENSG00000131187 (Ensembl)
Guanosine triphosphateMetaboliteCHEBI:15996 (ChEBI)
Guanylate cyclaseProteinA0A140VJE6 (Uniprot-TrEMBL)
IL1AGeneProductIL1A (HGNC)
IL1BGeneProductIL1B (HGNC)
KLK1GeneProductENSG00000167748 (Ensembl)
KLKB1GeneProductENSG00000164344 (Ensembl)
KNG1GeneProduct3827 (Entrez Gene)
Kallikrein-Kinin SystemPathway
L-arginineMetaboliteCHEBI:16467 (ChEBI)
MAPK1GeneProductENSG00000100030 (Ensembl)
MLCPComplex3.1.3.53 (BRENDA)
NFKB1GeneProductENSG00000109320 (Ensembl)
NFKB1GeneProductNFKB1 (HGNC)
NOS1GeneProductENSG00000089250 (Ensembl)
NOS3GeneProductENSG00000164867 (Ensembl)
PRKG1GeneProductENSG00000185532 (Ensembl)
Prostaglandin E2Metabolite363-24-6 (CAS)
Prostaglandin I2Metabolite35121-78-9 (CAS)
RENGeneProduct5972 (Entrez Gene)
RHOAGeneProductENSG00000067560 (Ensembl)
ROCK1GeneProductENSG00000067900 (Ensembl)
RelaxationPathway
SERPINE1GeneProduct5054 (Entrez Gene) SERPINE1 codes for plasminogen activator inhibitor-1 (PAI-1)
SERPING1GeneProductENSG00000149131 (Ensembl)
TNFGeneProductENSG00000232810 (Ensembl)
VDRGeneProductENSG00000111424 (Ensembl)
Vitamin D3MetaboliteCHEBI:28940 (ChEBI)
bradykinin, des-arg(9)MetaboliteCHEBI:133068 (ChEBI)
nitric oxideMetaboliteCHEBI:16480 (ChEBI)

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP4969"
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