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KALLIKREIN-KININ CASCADE PATHWAY (PW:0000526)

View Ontology Report

Description

Kallikrein-kinin (KKS) cascade pathway leads to the production of active kinin peptides whose signaling via two G-protein coupled (GPCR) receptors prompts a range of responses that include vasodilation, release of inflammatory mediators, stimulation of sensory neurons. Recent studies also point to a potential role in oxidative stress. All active peptides are derived from a single precursor - kininogen (Kng1). Alternative splicing of Kng1 gives rise to the high- and low-molecular weight kinino

Pathway Diagram:

Elsevier Inc. Bdkrb2 Bdkrb1 KD ---> vasodilation KD ---> inflammatory mediators release kinin signaling pathway Kng1 des-Arg-kinins ---> vasodilation inflammatory mediators release des-Arg-kinins ---> sensory neuron stimulation vasodilation sensory neuron stimulation KD BK lowKng1 highKng1 Serping1 Serping1 ---| Klkb1 Serping1 ---| F12a KD ---> des-Arg-kinins Bdkrb2 ---- KD Bdkrb1 ---- des-Arg-kinins des-Arg-kinins ---> inactive kinins pKlkb1 highKng1 ---- pKlkb1 F12 --+> F12a F12 Kng1 ---> highKng1 F12a BK ---> inactive kinins KD ---> inactive kinins Kng1 ---> lowKng1 coagulation cascade pathway classical complement pathway Serpina4 Prcp Klkb1 Klk1 Cpn1 Cpm A2m Klkb1 --+> F12a F12a --+> coagulation cascade pathway F12a --+> classical complement pathway A2m ---| Klkb1 F12a --+> Klkb1 Prcp --+> Klkb1 lowKng1 ---> KD highKng1 ---> BK Serpina4 ---| Klk1 BK ---> des-Arg-kinins BK ---> vasodilation BK ---> inflammatory mediators release KD ---> sensory neuron stimulation BK ---> sensory neuron stimulation des-Arg-kinins ---> inflammatory mediators release inactive kinins kininases des-Arg-kinins Bdkrb2 ---- BK
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Genes in Pathway:

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kallikrein-kinin cascade pathway term browser
Symbol Object Name Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G A2m alpha-2-macroglobulin ISO RGD PMID:16177542 RGD:7401223 NCBI chr 4:154,897,770...154,947,787
Ensembl chr 4:154,897,877...154,947,786
JBrowse link
G Ace angiotensin I converting enzyme ISO RGD PMID:16177542 RGD:7401223 NCBI chr10:90,910,316...90,930,437
Ensembl chr10:90,910,316...90,931,131
JBrowse link
G Bdkrb1 bradykinin receptor B1 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 6:124,510,827...124,514,475
Ensembl chr 6:124,510,870...124,513,747
JBrowse link
G Bdkrb2 bradykinin receptor B2 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 6:124,472,317...124,502,497
Ensembl chr 6:124,472,566...124,502,497
JBrowse link
G Cpm carboxypeptidase M ISO RGD PMID:16177542 RGD:7401223 NCBI chr 7:53,225,647...53,286,220
Ensembl chr 7:53,225,696...53,286,220
JBrowse link
G Cpn1 carboxypeptidase N subunit 1 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 1:242,844,575...242,873,465
Ensembl chr 1:242,844,212...242,873,465
JBrowse link
G F12 coagulation factor XII ISO RGD PMID:16177542 RGD:7401223 NCBI chr17:9,207,683...9,215,530
Ensembl chr17:9,207,683...9,215,530
JBrowse link
G Klk1 kallikrein 1 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 1:94,642,722...94,646,714
Ensembl chr 1:94,642,687...94,646,754
JBrowse link
G Klkb1 kallikrein B1 ISO RGD PMID:18396440 PMID:16177542 RGD:7401224, RGD:7401223 NCBI chr16:46,958,634...46,982,054
Ensembl chr16:46,958,707...46,982,053
JBrowse link
G Kng2 kininogen 2 ISO RGD PMID:16177542 RGD:7401223 NCBI chr11:77,913,876...77,936,247 JBrowse link
G Mme membrane metallo-endopeptidase ISO RGD PMID:16177542 RGD:7401223 NCBI chr 2:147,686,913...147,803,808
Ensembl chr 2:147,722,086...147,803,792
JBrowse link
G Prcp prolylcarboxypeptidase ISO RGD PMID:18396440 RGD:7401224 NCBI chr 1:146,931,487...146,983,891
Ensembl chr 1:146,930,561...146,984,530
JBrowse link
G Serpina4 serpin family A member 4 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 6:122,999,970...123,009,083
Ensembl chr 6:122,999,900...123,009,082
JBrowse link
G Serping1 serpin family G member 1 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 3:69,842,726...69,852,583
Ensembl chr 3:69,842,739...69,852,034
JBrowse link
G Xpnpep1 X-prolyl aminopeptidase 1 ISO RGD PMID:16177542 RGD:7401223 NCBI chr 1:252,001,366...252,052,077
Ensembl chr 1:252,001,367...252,051,479
JBrowse link
G Xpnpep2 X-prolyl aminopeptidase 2 ISO RGD PMID:16177542 RGD:7401223 NCBI chr  X:127,287,765...127,317,036
Ensembl chr  X:127,287,979...127,317,223
JBrowse link
kinin signaling pathway term browser
Symbol Object Name Evidence Notes Source PubMed Reference(s) RGD Reference(s) Position
G Arrb1 arrestin, beta 1 ISO RGD PMID:21145390 RGD:7411621 NCBI chr 1:153,837,964...153,912,111
Ensembl chr 1:153,838,078...153,904,061
JBrowse link
G Arrb2 arrestin, beta 2 ISO RGD PMID:21145390 RGD:7411621 NCBI chr10:55,146,887...55,154,854
Ensembl chr10:55,146,818...55,154,850
JBrowse link
G Bdkrb1 bradykinin receptor B1 ISO RGD PMID:16177542 PMID:15734727 RGD:7401223, RGD:7401225 NCBI chr 6:124,510,827...124,514,475
Ensembl chr 6:124,510,870...124,513,747
JBrowse link
G Bdkrb2 bradykinin receptor B2 ISO
TAS
RGD PMID:16177542 PMID:15734727 RGD:7401223, RGD:7401225 NCBI chr 6:124,472,317...124,502,497
Ensembl chr 6:124,472,566...124,502,497
JBrowse link
G Grk4 G protein-coupled receptor kinase 4 ISO RGD PMID:15734727 RGD:7401225 NCBI chr14:75,998,554...76,080,808
Ensembl chr14:76,006,218...76,080,693
JBrowse link
G Kng2 kininogen 2 ISO RGD PMID:16177542 RGD:7401223 NCBI chr11:77,913,876...77,936,247 JBrowse link

Additional Elements in Pathway:

(includes Gene Groups, Small Molecules, Other Pathways..etc.)
Object TypePathway ObjectPathway Object Description
Functional Classkininasesthe kinin peptides metabolizing enzymes

Pathway Gene Annotations

Disease Annotations Associated with Genes in the kallikrein-kinin cascade pathway
Disease TermsGene Symbols
3MC syndrome 1Kng2
abdominal aortic aneurysmAce
acquired angioedemaF12 , Kng2 , Serping1 , Xpnpep2
Acute Coronary SyndromeF12
Acute HepatitisAce
acute kidney failureA2m , Ace , Bdkrb2 , Klk1 , Kng2
Acute Lung InjuryAce , Serping1
acute myeloid leukemiaBdkrb1 , Bdkrb2
acute myocardial infarctionSerping1
acute necrotizing pancreatitisSerping1
adenocarcinomaAce
adult respiratory distress syndromeAce
AlbuminuriaAce
alcoholic cardiomyopathyAce
Alcoholic Liver DiseasesAce
Allanson Pantzar McLeod SyndromeAce
allergic diseaseAce , Kng2
allergic rhinitisAce
Alzheimer's diseaseA2m , Ace , Mme
AnaphylaxisKng2
anemiaAce
angioedemaF12 , Serping1 , Xpnpep2
Angiotensin I-Converting Enzyme, Benign Serum IncreaseAce
Animal Disease ModelsBdkrb2 , Kng2
Animal Mammary NeoplasmsKng2
ankylosing spondylitisAce
Aortic CoarctationAce
Arteriovenous FistulaAce
aspiration pneumoniaAce
asthmaAce , Bdkrb2
atrial fibrillationAce
autism spectrum disorderKlkb1
autistic disorderAce , Klkb1 , Xpnpep2
autosomal dominant polycystic kidney diseaseSerping1
autosomal recessive polycystic kidney diseaseAce
background diabetic retinopathyA2m
Banti's SyndromeAce
Behcet's diseaseAce
berylliosisAce
bilirubin metabolic disorderF12
bipolar disorderAce
BradycardiaKng2
brain ischemiaAce
breast cancerAce
Breast NeoplasmsMme
bronchiolitis obliteransAce
BurnsA2m , Serping1
C1 inhibitor deficiencyF12
CAKUTAce
carboxypeptidase N deficiencyCpn1
Cardiac ArrhythmiasAce , Kng2
CardiomegalyA2m , Ace , Klk1
cardiomyopathyBdkrb2 , Klk1
cardiovascular system diseaseAce
carotid artery diseaseAce
carotid artery thrombosisKlkb1
celiac diseaseAce
cerebellar ataxia type 43Mme
cerebral amyloid angiopathyMme
Cerebral HemorrhageAce
cerebral infarctionA2m , Ace , Serping1
Charcot-Marie-Tooth disease axonal type 2TMme
Chemical and Drug Induced Liver InjuryAce , Bdkrb2 , Kng2 , Serping1
chemical colitisAce
Chemotherapy-Induced Febrile NeutropeniaAce
cholestasisAce
Chronic Hepatitis CAce
Chronic Intermittent HypoxiaAce
chronic kidney diseaseKlk1
chronic myeloid leukemiaAce
chronic obstructive pulmonary diseaseAce , Bdkrb2
Colonic NeoplasmsA2m
Complement Component 4, Partial Deficiency OfSerping1
congenital diaphragmatic herniaAce
Congenital Hepatic FibrosisAce
congestive heart failureAce , Mme
coronary artery diseaseAce
Coronary DiseaseAce , F12
coronary restenosisAce
Coronavirus infectious diseaseAce
CoughAce , Bdkrb2 , Kng2
COVID-19A2m , Ace , Mme , Serping1
Cryopyrin-Associated Periodic SyndromesMme
Cytomegalovirus InfectionsAce
DeathF12
Diabetes ComplicationsBdkrb1 , Bdkrb2
diabetic angiopathyAce , Bdkrb1
Diabetic CardiomyopathiesA2m , Ace , Klk1
Diabetic NephropathiesAce , Bdkrb2 , Klk1 , Klkb1 , Kng2
diabetic neuropathyBdkrb1 , Mme
diabetic retinopathyAce , Bdkrb1 , Serpina4
diarrheaMme
diastolic heart failureAce
dilated cardiomyopathyAce
drug allergyAce
Drug EruptionsKng2
EdemaBdkrb1 , Kng2
end stage renal diseaseAce , Bdkrb1 , Klk1
endometriosisCpm
endomyocardial fibrosisAce
EndotoxemiaAce , F12 , Mme , Serping1
EnterocolitisKlkb1
EosinophiliaBdkrb2 , Kng2
epilepsyBdkrb1 , Bdkrb2
essential thrombocythemiaBdkrb1 , Bdkrb2
Experimental ArthritisA2m , Ace , Bdkrb1 , Klkb1 , Kng2
Experimental Autoimmune EncephalomyelitisA2m
Experimental ColitisAce
Experimental Diabetes MellitusAce , Bdkrb1 , Bdkrb2 , Klk1
Experimental Liver CirrhosisA2m , Ace , Kng2 , Mme , Serpina4 , Xpnpep2
Experimental Liver NeoplasmsF12
Extravasation of Diagnostic and Therapeutic MaterialsBdkrb2 , Kng2
extrinsic allergic alveolitisAce
Fabry diseaseAce
factor XI deficiencyKlkb1
factor XII deficiencyF12
Familial Cerebral Cavernous MalformationAce
familial Mediterranean feverAce
Femur Head NecrosisA2m
Fetal DeathAce
Fetal Growth RetardationAce
FeverA2m
FibrosisBdkrb1 , Klk1
focal segmental glomerulosclerosisBdkrb1
focal segmental glomerulosclerosis 1Ace
gallbladder adenocarcinomaAce
Gaucher's diseaseAce
genetic diseaseMme
Genetic Predisposition to DiseaseAce
glioblastomaSerping1
glomerulonephritisAce , Bdkrb1 , Klkb1
glomerulosclerosisAce
glycogen storage disease VAce
heart diseaseA2m
heart valve diseaseAce
Helicobacter InfectionsAce
hemolytic anemiaA2m
HemorrhageBdkrb2
hemorrhagic diseaseKlkb1
Henoch-Schoenlein purpuraAce , Kng2
hepatitis AAce
hepatocellular adenomaA2m
hepatocellular carcinomaA2m , Ace , Mme , Serpina4
hereditary angioedemaF12 , Kng2 , Serping1
Hereditary Angioedema 6Kng2
hereditary angioedema type IF12 , Serping1
hereditary angioedema type IIIF12
hereditary breast ovarian cancer syndromeMme
high grade gliomaBdkrb2
high molecular weight kininogen deficiencyKng2
Hirschsprung's diseaseA2m
Human InfluenzaSerping1
HyperalgesiaBdkrb1 , Bdkrb2 , Kng2
HyperemiaBdkrb2 , Kng2
HyperesthesiaKng2
hyperhomocysteinemiaF12
HyperoxiaAce
hypertensionAce , Bdkrb1 , Bdkrb2 , F12 , Klk1 , Klkb1 , Kng2 , Mme
Hypertensive NephrosclerosisAce
hypertrophic cardiomyopathyAce
HypoalbuminemiaA2m
Hypoglossal Nerve InjuriesMme
hypophosphatemic nephrolithiasis/osteoporosisF12
hypophosphatemic nephrolithiasis/osteoporosis 1F12
HypotensionAce , Bdkrb2 , Kng2
HypoxiaMme
IgA glomerulonephritisAce
in situ carcinomaAce
InflammationA2m , Bdkrb1 , Bdkrb2 , Klk1 , Serping1
inflammatory bowel diseaseKlkb1
Insulin ResistanceAce , Bdkrb1 , Klk1
intellectual disabilityPrcp , Serping1
intermediate coronary syndromeAce
Intestinal Reperfusion InjuryAce
intracranial aneurysmAce
Intracranial HemorrhagesSerping1
Kallikrein, Decreased Urinary Activity ofKlk1
kidney diseaseAce
kidney failureAce , Mme
Kidney Reperfusion InjuryAce , Bdkrb1
Left Ventricular HypertrophyAce , Bdkrb1 , Bdkrb2
leukemiaAce
LeukocytosisKng2
leukostasisAce
liver cirrhosisA2m , Ace , Klkb1 , Serping1
Liver MetastasisAce
Liver Reperfusion InjurySerping1
lung cancerAce
lung carcinomaAce
lung diseaseA2m , Ace , Bdkrb2
Lung InjuryAce , Mme
Lung NeoplasmsA2m , Ace , Serping1
lupus nephritisKlkb1 , Serping1
macular degenerationSerping1
malariaAce
male infertilityAce
malignant mesotheliomaSerpina4
Marfanoid Mental Retardation Syndrome, AutosomalF12
membranous glomerulonephritisA2m , Mme
Memory DisordersAce
Meningococcal InfectionsAce
microcephalyAce
Microvascular AnginaBdkrb1 , Bdkrb2
middle cerebral artery infarctionAce , F12
mitral valve diseaseAce
mitral valve prolapseAce
multiple myelomaAce
multiple sclerosisA2m
Mycobacterium InfectionsAce
myelofibrosisBdkrb1 , Bdkrb2
myocardial infarctionAce , Bdkrb1 , Bdkrb2 , F12 , Klk1
Myocardial Reperfusion InjuryKng2 , Serping1
myocarditisAce
Neoplasm MetastasisAce
neovascular inflammatory vitreoretinopathyKng2
nephritisAce , Bdkrb1
nephrosisAce
nephrotic syndromeA2m , Ace
neuropathyMme
non-alcoholic fatty liver diseaseAce
non-arteritic anterior ischemic optic neuropathyAce
obesityAce , Bdkrb1
obstructive lung diseaseA2m
obstructive sleep apneaAce
occupational dermatitisBdkrb2 , Kng2
ocular hypotensionAce
osteoporosisAce
otitis mediaA2m
Otitis Media with EffusionA2m
Overactive Urinary BladderBdkrb1
PainAce , Bdkrb1 , Bdkrb2 , Kng2
pancreatic cancerAce
pancreatic ductal carcinomaAce
pancreatitisBdkrb2 , Klk1 , Serping1
Parkinson's diseaseA2m , Ace
periodontitisMme
peripheral nervous system diseaseMme
Peritoneal FibrosisAce
peritonitisA2m
Pleural EffusionAce
pleurisyBdkrb1 , Bdkrb2
Pneumococcal MeningitisSerping1
pneumoniaAce , Bdkrb2
polycythemiaAce
portal hypertensionBdkrb2
pre-eclampsiaAce
pre-malignant neoplasmAce
Pregnancy-Induced HypertensionAce
Prekallikrein DeficiencyKlkb1
Premature Infant DiseasesAce
primary biliary cholangitisAce
primary ovarian insufficiencyXpnpep2
Prostatic NeoplasmsAce , Mme
proteinuriaAce
pulmonary embolismKlkb1
pulmonary fibrosisAce , Bdkrb1
pulmonary hypertensionAce , Bdkrb2
Puromycin Aminonucleoside NephrosisAce
pyelonephritisAce
Radiation NephropathyAce
renal fibrosisAce , Bdkrb1
Renal Tubular DysgenesisAce
renovascular hypertensionAce
Reperfusion InjuryAce , Klk1 , Serping1
respiratory system diseaseAce
rheumatoid arthritisA2m , Bdkrb2
rhinitisBdkrb1 , Bdkrb2
Right Ventricular HypertrophyAce
sarcoidosisAce
schizophreniaAce
sciatic neuropathyBdkrb1 , Bdkrb2
SepsisA2m , Ace , Klkb1
severe acute respiratory syndromeAce
silicosisCpm
Skeletal Muscle Reperfusion InjurySerping1
Spinocerebellar AtaxiasMme
SplenomegalyBdkrb1
Spontaneous AbortionsF12
Staphylococcal InfectionsAce
stomach cancerAce
Stomach NeoplasmsAce
StrokeAce , F12 , Kng2
subacute sclerosing panencephalitisAce
substance-induced psychosisAce
Sudden Cardiac DeathKng2
Sudden DeathAce
suppurative otitis mediaA2m
syndromic X-linked intellectual disability Lubs typeXpnpep2
syndromic X-linked intellectual disability Raymond typeXpnpep2
systemic lupus erythematosusAce , Klkb1
systemic sclerodermaAce
TachycardiaKng2
temporal lobe epilepsyBdkrb1 , Bdkrb2
thrombocytopeniaKlkb1
ThromboembolismF12
thrombosisBdkrb2 , Klkb1
toxic shock syndromeA2m , Ace , Serping1
transient cerebral ischemiaF12
Traumatic ShockSerping1
trypanosomiasisA2m
type 1 diabetes mellitusAce
type 2 diabetes mellitusAce , F12
ureteral obstructionAce
urticariaF12
uveitisAce
Vascular System InjuriesAce , Bdkrb1 , Bdkrb2
Venous ThromboembolismAce , Kng2
Venous ThrombosisF12
Ventricular FibrillationAce
Ventricular RemodelingAce
viral pneumoniaAce
Weight GainAce
Weight LossAce
Wilson diseaseA2m
Pathway Annotations Associated with Genes in the kallikrein-kinin cascade pathway
Pathway TermsGene Symbols
acenocoumarol pharmacodynamics pathwayF12 , Klkb1
alteplase pharmacodynamics pathwayF12 , Klkb1
Alzheimer's disease pathwayA2m , Mme
aminocaproic acid pharmacodynamics pathwayF12 , Klkb1
angiotensin (1-7) signaling pathwayAce , Mme
angiotensin II signaling pathwayAce
anistreplase pharmacodynamics pathwayF12 , Klkb1
aprotinin pharmacodynamics pathwayF12 , Klkb1
argatroban pharmacodynamics pathwayF12 , Klkb1
benazepril pharmacodynamics pathwayAce
benazepril pharmacokinetics pathwayAce
bivalirudin pharmacodynamics pathwayF12 , Klkb1
calcium/calcium-mediated signaling pathwayBdkrb1 , Bdkrb2
candesartan pharmacodynamics pathwayAce
captopril pharmacodynamics pathwayAce
Chagas disease pathwayAce , Bdkrb2
cilazapril pharmacodynamics pathwayAce
cilazapril pharmacokinetics pathwayAce
coagulation cascade pathwayA2m , Bdkrb1 , Bdkrb2 , F12 , Klkb1 , Kng2 , Serping1
complement system pathwayA2m , Bdkrb1 , Bdkrb2 , F12 , Klkb1 , Kng2 , Serping1
dicoumarol pharmacodynamics pathwayF12 , Klkb1
enalapril pharmacodynamics pathwayAce
enalapril pharmacokinetics pathwayAce
enoxaparin pharmacodynamics pathwayF12 , Klkb1
eprosartan pharmacodynamics pathwayAce
fondaparinux pharmacodynamics pathwayF12 , Klkb1
forasartsn pharmacodynamics pathwayAce
fosinopril pharmacodynamics pathwayAce
fosinopril pharmacokinetics pathwayAce
G protein mediated signaling pathway via Galphai familyBdkrb1 , Bdkrb2
G protein mediated signaling pathway via Galphaq familyBdkrb1 , Bdkrb2
heparin pharmacodynamics pathwayF12 , Klkb1
hypertrophic cardiomyopathy pathwayAce
immune response pathwayA2m
inflammatory response pathwayA2m
interleukin-6 signaling pathwayA2m
irbesartan pharmacodynamics pathwayAce
kallikrein-kinin cascade pathwayA2m , Ace , Bdkrb1 , Bdkrb2 , Cpm , Cpn1 , F12 , Klk1 , Klkb1 , Kng2 , Mme , Prcp , Serpina4 , Serping1 , Xpnpep1 , Xpnpep2
kinin signaling pathwayBdkrb1 , Bdkrb2 , Kng2
lisinopril pharmacodynamics pathwayAce
losartan pharmacodynamics pathwayAce
moexipril pharmacodynamics pathwayAce
moexipril pharmacokinetics pathwayAce
olmesartan pharmacodynamics pathwayAce
perindopril pharmacodynamics pathwayAce
phenindione pharmacodynamics pathwayF12 , Klkb1
quinapril pharmacodynamics pathwayAce
quinapril pharmacokinetics pathwayAce
ramipril pharmacodynamics pathwayAce
ramipril pharmacokinetics pathwayAce
renin-angiotensin cascade pathwayAce , Mme
reteplase pharmacodynamics pathwayF12 , Klkb1
spirapril pharmacodynamics pathwayAce
spirapril pharmacokinetics pathwayAce
syndecan signaling pathwayKng2
telmisartan pharmacodynamics pathwayAce
trandolapril pharmacodynamics pathwayAce
trandolapril pharmacokinetics pathwayAce
tranexamic acid pharmacodynamics pathwayF12 , Klkb1
transforming growth factor-beta Smad dependent signaling pathwayA2m
valsartan pharmacodynamics pathwayAce
warfarin pharmacodynamics pathwayF12 , Klkb1
Phenotype Annotations Associated with Genes in the kallikrein-kinin cascade pathway

References Associated with the kallikrein-kinin cascade pathway:

Ontology Path Diagram:

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Import into Pathway Studio: