Received October 22, 2004
Revised December 1, 2004
Accepted after revision December 14, 2004

¹ Medical University of South Carolina

^* To whom correspondence should be addressed. E-mail: chaoj{at}musc.edu.

	Abstract

SUMMARY Tissue kallikrein, a serine proteinase, produces the potent vasodilator kinin peptide from kininogen substrate. The levels of tissue kallikrein are reduced in humans and animal models with hypertension, cardiovascular and renal disease. Using transgenic and somatic gene transfer approaches, we investigated the role of the tissue kallikrein-kinin 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/kinin levels after gene transfer exerted beneficial effects in protection against cardiac remodeling, renal injuries, restenosis, cerebral infarction and neurological deficits in normotensive animal models without hemodynamic effects, indicating direct actions of kallikrein independent of its ability to lower blood pressure. These kallikrein's effects were mediated by the kinin B2 receptor, as icatibant abolished the actions of kallikrein. Moreover, kallikrein/kinin had pleiotropic effects in 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 activation and inflammatory cytokine levels. These results indicate a novel role of kallikrein/kinin through the kinin B2 receptor as an anti-oxidant and anti-inflammatory 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-stage renal disease and stroke in humans. Key words: tissue kallikrein, kinin, gene therapy, protein infusion, hypertension, oxidative stress, inflammation, heart, kidney, blood vessel, brain

Key Words: Bradykinin, Hypertension, Inflammation