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Using transgenic and somatic gene transfer approaches, we investigated the role of the tissue kallikrein\u2013kinin system in cardiovascular, renal and central nervous systems. A single injection of the human tissue kallikrein gene in plasmid DNA or an adenoviral vector resulted in a prolonged reduction of blood pressure and attenuation of hypertrophy and fibrosis in the heart and kidney of several hypertensive animal models. Furthermore, enhanced kallikrein\u2013kinin levels after gene transfer exerted beneficial effects, with protection against cardiac remodelling, renal injuries, restenosis, cerebral infarction and neurological deficits in normotensive animal models without haemodynamic effects, indicating direct actions of kallikrein independent of its ability to lower blood pressure. The effects of kallikrein were mediated by the kinin B2 receptor, as the specific B2 receptor antagonist icatibant abolished the actions of kallikrein. Moreover, kallikrein\u2013kinin exhibited pleiotropic effects by inhibiting apoptosis, inflammation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in the heart, kidney, brain and blood vessel. Exogenous administration of kallikrein also led to increased nitric oxide (NO)\/cGMP and cAMP levels, and reduced NAD(P)H oxidase activities, superoxide formation and pro\u2010inflammatory cytokine levels. These results indicate a novel role of kallikrein\u2013kinin through the kinin B2 receptor as an antioxidant and anti\u2010inflammatory agent in protection against stroke, cardiovascular and renal disease, and may uncover new drug targets for the prevention and treatment of heart failure, vascular injury, end\u2010stage renal disease and stroke in humans.<\/jats:bold><\/jats:p>","DOI":"10.1113\/expphysiol.2004.028464","type":"journal-article","created":{"date-parts":[[2005,1,15]],"date-time":"2005-01-15T01:14:40Z","timestamp":1105751680000},"page":"291-298","source":"Crossref","is-referenced-by-count":88,"title":["Kallikrein\u2013kinin in stroke, cardiovascular and renal 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