Adenovirus-Mediated Human Kallikrein Gene Delivery Increases Endogenous Rat Tissue Kallikrein in Hypertensive Rat Models

Abstract

P201 Our recent studies showed that adenovirus-mediated human tissue kallikrein gene delivery attenuated hypertension, cardiac hypertrophy, and renal injury in various hypertensive rat models. However, mechanisms underlying the beneficial effects of human kallikrein gene delivery are not clear. In the present study, we investigated the potential of human kallikrein gene delivery on synthesis and excretion of endogenous rat tissue kallikrein in normotensive and hypertensive rat models. Adenovirus carrying the human kallikrein cDNA under the control of cytomegalovirus (CMV) promoter/enhancer was administered via tail vein injection. Control rats received adenovirus harboring the b-galactosidase or luciferase gene under control of the CMV promoter/enhancer. A single injection of the human tissue kallikrein gene caused a prolonged blood pressure-lowering effect in spontaneously hypertensive rats, two kidney-one clip, Dahl salt-sensitive, deoxycorticosterone acetate-salt and monocrotaline-induced pulmonary hypertensive rats, while systolic blood pressure of normotensive Sprague-Dawley rats remained unaltered. Human kallikrein gene delivery significantly increased endogenous rat tissue kallikrein levels in the kidney and urine of different models of hypertensive rats as compared with their respective controls. However, urinary excretion of rat tissue kallikrein was not affected by human kallikrein gene delivery in normotensive rats. The endogenous rat tissue kallikrein mRNA expression in the kidney remained unaltered after human kallikrein gene delivery, which indicated that expression of human kallikrein in hypertensive rats increased endogenous rat kallikrein synthesis and excretion. These findings indicate that beneficial effects of human kallikrein gene delivery in hypertensive rat models are mediated, at least in part, by enhanced endogenous tissue kallikrein-kinin system.