The tissue kallikrein-kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction.
Tissue kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human tissue kallikrein or kinin B2 receptor are permanently hypotensive, and somatic kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, tissue kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that tissue kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.
Chao
Julie
J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA. chaoj@musc.edu
Bledsoe
Grant
G
Yin
Hang
H
Chao
Lee
L
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D016234:Kallikrein-Kinin System / Q000502:physiology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020840:Tissue Kallikreins / Q000378:metabolism / Q000627:therapeutic use*
D020840:Tissue Kallikreins