RAS and bradykinin pathways in COVID-19 (Homo sapiens)

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116201313132, 16Blood vesselDegradationSensitization20-HETEVitamin D3Complement andCoagulation Cascadesbradykinin, des-arg(9)KLKB1VDRKLK1CYP24A1CPN1NFKB1MAPK1L-arginineSERPING1AldosteroneKallikrein-KininSystemAGTR1SERPINE1F12131313AGTR218BDKRB1BradykininAngiotensin IIKNG1Angiotensin IACEAng 1-7RENACE2AGT15ACEBDKRB214Ang 1-9Arachidonic acidCa++CYP3A4CYP3A4ACERelaxationPRKG1MLCPGuanylate cyclaseRHOAROCK1Guanosine triphosphatenitric oxideVascular smooth muscle cellCyclic guanosine monophosphate7, 10-12nitric oxideNOS1NOS311L-arginineInflammatory mediatorsACE2TNF6IL1AProstaglandin E2Prostaglandin I2NFKB1IL1BIL1AIL1BProstaglandin E2Prostaglandin I2IL1AIL1BIncreased plasminogen activator inhibitor-1 (PAI-1 coded by SERPINE1) totissue/urokinase plasminogen activator (tPA/uPA) ratio leading to hypofibrinolysis


Description

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

The expression of several genes in this pathway 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.

Quality Tags

Ontology Terms

 

Bibliography

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  1. Surks HK; ''cGMP-dependent protein kinase I and smooth muscle relaxation: a tale of two isoforms.''; Circ Res, 2007 PubMed Europe PMC Scholia
  2. 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
  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. 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
  6. 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
  7. Denninger JW, Marletta MA; ''Guanylate cyclase and the .NO/cGMP signaling pathway.''; Biochim Biophys Acta, 1999 PubMed Europe PMC Scholia
  8. 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
  9. 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
  10. Surks HK; ''cGMP-dependent protein kinase I and smooth muscle relaxation: a tale of two isoforms.''; Circ Res, 2007 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. Denninger JW, Marletta MA; ''Guanylate cyclase and the .NO/cGMP signaling pathway.''; Biochim Biophys Acta, 1999 PubMed Europe PMC Scholia
  13. ''''; , PubMed Europe PMC Scholia
  14. Schwartz GL, Turner ST; ''Pharmacogenetics of antihypertensive drug responses.''; Am J Pharmacogenomics, 2004 PubMed Europe PMC Scholia
  15. Ferreira AJ, Raizada MK; ''Are we poised to target ACE2 for the next generation of antihypertensives?''; J Mol Med, 2008 PubMed Europe PMC Scholia
  16. 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
  17. 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
  18. Weir MR; ''Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?''; Clin Ther, 2007 PubMed Europe PMC Scholia
  19. 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
  20. 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

History

View all...
CompareRevisionActionTimeUserComment
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)
Ca++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

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