EXPERIMENTAL KALLIKREIN GENE THERAPY IN HYPERTENSION, CARDIOVASCULAR AND RENAL DISEASES

Abstract Hypertension is a multi-gene and multi-factorial disorder affecting about 25% of the population. Hypertensive subjects are more likely to develop other cardiovascular diseases such as peripheral vascular disease, coronary heart disease, congestive heart failure and cerebrovascular disease. To demonstrate potential therapeutic effects of somatic gene delivery in treating hypertension, we delivered human tissue kallikrein in the form of naked DNA or in an adenovirus vector into hypertensive rats. Naked DNA constructs were delivered into spontaneously hypertensive rats via intramuscular, intravenous, intraportal vein and intraperitoneal routes. A single injection of human kallikrein DNA construct caused a sustained reduction of blood pressure which began 1 week post-injection and continued for more than 6 weeks. The hypotensive effect caused by somatic gene delivery of human tissue kallikrein in hypertensive rats is reversed by aprotinin, a potent tissue kallikrein inhibitor. Both systemic and local delivery of the human tissue kallikrein gene in an adenovirus vector were found to be highly effective in producing a rapid and sustained reduction of blood pressure in hypertensive rat models such as spontaneously hypertensive rats; two kidney, one clip Goldblatt hypertensive rats; and Dahl salt-sensitive rats. The expression of human tissue kallikrein in rats was identified in the heart, kidney, aorta, lung and liver by reverse transcription-polymerase chain reaction followed by Southern blot analysis and by ELISA. Adenovirus-mediated kallikrein gene delivery also resulted in the attenuation of glomerular and tubular damage and reduction of the left ventricular mass and cardiomyocyte size in Dahl salt-sensitive rats fed a high salt diet. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating salt-related hypertension as well as cardiovascular and renal diseases. These results suggest the feasibility of applying somatic gene therapy for treating hypertension and salt-related cardiovascular and renal disorders.