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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

Genes in Pathway:

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kallikrein-kinin cascade pathway term browser
Symbol Object Name JBrowse Chr Start Stop Reference
G A2m alpha-2-macroglobulin JBrowse link 4 154,309,426 154,359,138 RGD:7401223
G Ace angiotensin I converting enzyme JBrowse link 10 94,170,766 94,213,831 RGD:7401223
G Bdkrb1 bradykinin receptor B1 JBrowse link 6 129,437,423 129,441,553 RGD:7401223
G Bdkrb2 bradykinin receptor B2 JBrowse link 6 129,399,468 129,429,676 RGD:7401223
G Cpm carboxypeptidase M JBrowse link 7 60,654,350 60,714,620 RGD:7401223
G Cpn1 carboxypeptidase N subunit 1 JBrowse link 1 263,733,887 263,762,758 RGD:7401223
G F12 coagulation factor XII JBrowse link 17 9,736,577 9,744,420 RGD:7401223
G Klk1 kallikrein 1 JBrowse link 1 100,131,562 100,135,556 RGD:7401223
G Klkb1 kallikrein B1 JBrowse link 16 50,151,127 50,175,407 RGD:7401224
G Kng2 kininogen 2 JBrowse link 11 81,509,185 81,516,759 RGD:7401223
G Prcp prolylcarboxypeptidase JBrowse link 1 157,701,089 157,750,177 RGD:7401224
G Serpina4 serpin family A member 4 JBrowse link 6 127,743,883 127,753,047 RGD:7401223
G Serping1 serpin family G member 1 JBrowse link 3 72,161,230 72,171,109 RGD:7401223
G Xpnpep1 X-prolyl aminopeptidase 1 JBrowse link 1 273,708,217 273,758,247 RGD:7401223
G Xpnpep2 X-prolyl aminopeptidase 2 JBrowse link X 134,940,656 134,969,874 RGD:7401223
kinin signaling pathway term browser
Symbol Object Name JBrowse Chr Start Stop Reference
G Arrb1 arrestin, beta 1 JBrowse link 1 164,502,099 164,573,947 RGD:7411621
G Arrb2 arrestin, beta 2 JBrowse link 10 57,040,252 57,048,045 RGD:7411621
G Bdkrb1 bradykinin receptor B1 JBrowse link 6 129,437,423 129,441,553 RGD:7401223
G Bdkrb2 bradykinin receptor B2 JBrowse link 6 129,399,468 129,429,676 RGD:7401223
G Grk4 G protein-coupled receptor kinase 4 JBrowse link 14 81,261,708 81,339,516 RGD:7401225
G Kng2 kininogen 2 JBrowse link 11 81,509,185 81,516,759 RGD:7401223

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
Abortion, SpontaneousF12
Acquired AngioedemaF12 , Kng2 , Serping1
Acute Coronary SyndromeF12
acute kidney failureA2m , Ace , Bdkrb2 , Klk1 , Kng2
Acute Lung InjurySerping1
acute myeloid leukemiaBdkrb1 , Bdkrb2
acute myocardial infarctionSerping1
Acute Necrotizing PancreatitisSerping1
adult respiratory distress syndromeAce
alcoholic cardiomyopathyAce
Allanson Pantzar McLeod SyndromeAce
allergic hypersensitivity diseaseAce , Kng2
allergic rhinitisAce
Alpha-2-Macroglobulin DeficiencyA2m
Alzheimer's diseaseA2m , Ace
Alzheimer's disease 1A2m
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 nonsyndromic deafness 7F12
autosomal recessive polycystic kidney diseaseAce
background diabetic retinopathyA2m
Behcet's diseaseAce
bilirubin metabolic disorderF12
bipolar disorderAce
brain ischemiaAce
breast cancerAce
bronchiolitis obliteransAce
BurnsA2m , Serping1
C1 inhibitor deficiencyF12
Carboxypeptidase N DeficiencyCpn1
Cardiac ArrhythmiasAce , Kng2
CardiomegalyA2m , Ace
cardiovascular system diseaseAce
carotid artery diseaseAce
carotid artery thrombosisKlkb1
Cerebral HemorrhageAce
cerebral infarctionA2m , Ace , Serping1
Chemical and Drug Induced Liver InjuryBdkrb2 , Kng2 , Serping1
Chemotherapy-Induced Febrile NeutropeniaAce
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
coronary artery diseaseAce
Coronary DiseaseAce , F12
coronary restenosisAce
Coronavirus InfectionsAce
CoughAce , Bdkrb2 , Kng2
Diabetes ComplicationsBdkrb1 , Bdkrb2
Diabetes Mellitus, Experimental Ace , Bdkrb1 , Bdkrb2 , Klk1
diabetic angiopathyBdkrb1
Diabetic CardiomyopathiesA2m , Ace , Klk1
Diabetic NephropathiesAce , Bdkrb2 , Klk1 , Klkb1 , Kng2
diabetic neuropathyBdkrb1
diabetic retinopathyAce , Bdkrb1 , Bdkrb2 , Serpina4
dilated cardiomyopathyAce
drug allergyAce
Drug EruptionsKng2
EdemaBdkrb1 , Kng2
end stage renal failureAce , Bdkrb1 , Klk1
endomyocardial fibrosisAce
EndotoxemiaAce , F12 , Serping1
EosinophiliaBdkrb2 , Kng2
epilepsyBdkrb1 , Bdkrb2
essential thrombocythemiaBdkrb1 , Bdkrb2
Experimental ArthritisA2m , Ace , Bdkrb1 , Klkb1 , Kng2
Experimental Autoimmune EncephalomyelitisA2m
Experimental Liver CirrhosisA2m , Kng2 , Serpina4 , Xpnpep2
Experimental Liver NeoplasmsF12
Extravasation of Diagnostic and Therapeutic MaterialsBdkrb2 , Kng2
extrinsic allergic alveolitisAce
Fabry diseaseAce
factor XII deficiencyF12
Familial Cerebral Cavernous MalformationAce
Femur Head NecrosisA2m
Fetal DeathAce
Fetal Growth RetardationAce
FibrosisBdkrb1 , Klk1
Flaujeac Factor DeficiencyKng2
focal segmental glomerulosclerosisBdkrb1
focal segmental glomerulosclerosis 1Ace
gallbladder adenocarcinomaAce
Gaucher's diseaseAce
Genetic Predisposition to DiseaseAce
glioblastoma multiformeSerping1
glomerulonephritisAce , Bdkrb1 , Klkb1
glycogen storage disease VAce
heart diseaseA2m
hemolytic anemiaA2m
Henoch-Schoenlein purpuraAce , Kng2
hepatocellular adenomaA2m
hepatocellular carcinomaA2m , Ace , Serpina4
hereditary angioedemaF12 , Kng2 , Serping1
Hereditary Angioedema Type IIIF12
Hereditary Angioedema Types I and IIF12 , Serping1
Human InfluenzaSerping1
HyperalgesiaBdkrb1 , Bdkrb2 , Kng2
HyperemiaBdkrb2 , Kng2
hypertensionAce , Bdkrb1 , Bdkrb2 , F12 , Klk1 , Klkb1 , Kng2
Hypertension, Pregnancy-InducedAce
Hypertensive NephrosclerosisAce
hypertrophic cardiomyopathyAce
Hypophosphatemic Nephrolithiasis/OsteoporosisF12
HypotensionAce , Bdkrb2 , Kng2
IgA glomerulonephritisAce
in situ carcinomaAce
InflammationA2m , Bdkrb1 , Bdkrb2 , Klk1 , Serping1
inflammatory bowel diseaseKlkb1
Insulin ResistanceAce , Bdkrb1
intermediate coronary syndromeAce
Intestinal Reperfusion InjuryAce
intracranial aneurysmAce
Intracranial HemorrhagesSerping1
Kallikrein, Decreased Urinary Activity ofKlk1
kidney diseaseAce
kidney failureAce
Kidney Reperfusion InjuryAce , Bdkrb1
Left Ventricular HypertrophyAce , Bdkrb1 , Bdkrb2
liver cirrhosisA2m , Klkb1 , Serping1
Liver Reperfusion InjurySerping1
lung cancerAce
lung diseaseA2m , Ace , Bdkrb2
Lung NeoplasmsA2m , Ace , Serping1
lupus nephritisKlkb1 , Serping1
macular degenerationSerping1
male infertilityAce
malignant gliomaBdkrb2
malignant mesotheliomaSerpina4
membranous glomerulonephritisA2m
Memory DisordersAce
Meningococcal InfectionsAce
Microvascular AnginaBdkrb1 , Bdkrb2
Microvascular Complications of Diabetes, Susceptibility to, 2Ace
Microvascular Complications of Diabetes, Susceptibility to, 3Ace
middle cerebral artery infarctionAce , F12
mitral valve prolapseAce
multiple myelomaAce
myelofibrosisBdkrb1 , Bdkrb2
myocardial infarctionAce , Bdkrb1 , Bdkrb2 , F12 , Klk1
Myocardial Reperfusion InjuryKng2 , Serping1
Neoplasm MetastasisAce
nephritisAce , Bdkrb1
Nephrosis, Puromycin AminonucleosideAce
nephrotic syndromeA2m , Ace
non-arteritic anterior ischemic optic neuropathyAce
nonalcoholic fatty liver diseaseAce
obesityAce , Bdkrb1
obstructive lung diseaseA2m
obstructive sleep apneaAce
occupational dermatitisBdkrb2 , Kng2
ocular hypotensionAce
Overactive Urinary BladderBdkrb1
PainAce , Bdkrb1 , Bdkrb2 , Kng2
pancreatic cancerAce
pancreatic ductal carcinomaAce
pancreatitisBdkrb2 , Klk1 , Serping1
Parkinson's diseaseA2m , Ace
Peritoneal FibrosisAce
pleurisyBdkrb1 , Bdkrb2
Pneumococcal MeningitisSerping1
pneumoniaAce , Bdkrb2
portal hypertensionBdkrb2
pre-malignant neoplasmAce
Prekallikrein DeficiencyKlkb1
Premature Infant DiseasesAce
premature ovarian failureXpnpep2
primary biliary cirrhosisAce
proliferative vitreoretinopathyKng2
Prostatic NeoplasmsAce
pulmonary embolismKlkb1
pulmonary fibrosisAce , Bdkrb1
pulmonary hypertensionAce , Bdkrb2
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
sciatic neuropathyBdkrb1 , Bdkrb2
sensorineural hearing lossAce
SepsisA2m , Klkb1
severe acute respiratory syndromeAce
Shock, TraumaticSerping1
Skeletal Muscle Reperfusion InjurySerping1
Staphylococcal InfectionsAce
Stomach NeoplasmsAce
StrokeAce , F12 , Kng2
substance-induced psychosisAce
Sudden DeathAce
Sudden Death, CardiacKng2
systemic lupus erythematosusAce , Klkb1
systemic sclerodermaAce
temporal lobe epilepsyBdkrb1 , Bdkrb2
thrombosisBdkrb2 , Klkb1
toxic shock syndromeA2m , Serping1
transient cerebral ischemiaF12
type 1 diabetes mellitusAce
type 2 diabetes mellitusAce , F12
ureteral obstructionAce
Vascular System InjuriesAce , Bdkrb1 , Bdkrb2
Venous ThromboembolismAce , Kng2
Venous ThrombosisF12
Ventricular FibrillationAce
Ventricular RemodelingAce
viral pneumoniaAce
Weight GainAce
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
aminocaproic acid pharmacodynamics pathwayF12 , Klkb1
angiotensin (1-7) signaling pathwayAce
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 , 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
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: