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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
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
Angioedema Induced by ACE InhibitorsXpnpep2
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
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
celiac diseaseAce
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 infectionAce
CoughAce , Bdkrb2 , Kng2
Diabetes ComplicationsBdkrb1 , Bdkrb2
Diabetes Mellitus, Experimental Ace , Bdkrb1 , Bdkrb2 , Klk1
diabetic angiopathyAce , Bdkrb1
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
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
high molecular weight kininogen deficiencyKng2
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
Marfanoid Mental Retardation Syndrome, AutosomalF12
membranous glomerulonephritisA2m
Memory DisordersAce
Meningococcal InfectionsAce
Microvascular AnginaBdkrb1 , Bdkrb2
middle cerebral artery infarctionAce , F12
mitral valve prolapseAce
multiple myelomaAce
myelofibrosisBdkrb1 , Bdkrb2
myocardial infarctionAce , Bdkrb1 , Bdkrb2 , F12 , Klk1
Myocardial Reperfusion InjuryKng2 , Serping1
Neoplasm MetastasisAce
neovascular inflammatory vitreoretinopathyKng2
nephritisAce , Bdkrb1
Nephrosis, Puromycin AminonucleosideAce
nephrotic syndromeA2m , Ace
non-alcoholic fatty liver diseaseAce
non-arteritic anterior ischemic optic neuropathyAce
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
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
SepsisA2m , Klkb1
severe acute respiratory syndromeAce
Shock, TraumaticSerping1
Skeletal Muscle Reperfusion InjurySerping1
Spontaneous AbortionsF12
Staphylococcal InfectionsAce
Stomach NeoplasmsAce
StrokeAce , F12 , Kng2
substance-induced psychosisAce
Sudden DeathAce
Sudden Death, CardiacKng2
syndromic X-linked intellectual disability Lubs typeXpnpep2
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:

paths to the root

Import into Pathway Studio:


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.