KALLIKREIN GENE DELIVERY ATTENUATES HYPERTENSION AND CARDIAC-HYPERTROPHY AND ENHANCES RENAL-FUNCTION IN GOLDBLATT HYPERTENSIVE RATS

To demonstrate potential therapeutic effects of kallikrein gene delive ry, we delivered adenovirus (Ad.CMV-cHK) carrying the human tissue kal likrein gene into two-kidney, one-clip Goldblatt hypertensive rats. A single intravenous injection of the recombinant adenovirus caused a de lay of blood pressure increase that began 1 day after injection and co ntinued for 24 days. A maximal blood pressure reduction was observed i n rats receiving kallikrein gene delivery compared with control rats r eceiving Ad.CMV-LacZ (160+/-5 versus 186+/-7 mm Hg, n=6, P<.01). The e xpression of human tissue kallikrein mRNA was identified in the kidney , heart, aorta, and liver of rats receiving kallikrein gene delivery. Immunoreactive human kallikrein levels were measured in rat serum and urine in a time-dependent manner. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in the left ventricular mass a nd cardiomyocyte size, as well as an increase in renal blood flow, uri ne flow, glomerular filtration rates, electrolyte output, and urine ex cretion, Enhanced renal responses were accompanied by significant incr eases in urinary kinin, nitrite/nitrate, and cyclic CMP levels. These findings show that the expression of human tissue kallikrein via gene delivery has protective effects against renovascular hypertension and cardiovascular and renal dysfunction.