Kallikrein Gene Delivery Attenuates Hypertension and Cardiac Hypertrophy and Enhances Renal Function in Goldblatt Hypertensive Rats

Abstract

Abstract —To demonstrate potential therapeutic effects of kallikrein gene delivery, we delivered adenovirus (Ad.CMV-cHK) carrying the human tissue kallikrein gene into two-kidney, one-clip Goldblatt hypertensive rats. A single intravenous injection of the recombinant adenovirus caused a delay of blood pressure increase that began 1 day after injection and continued for 24 days. A maximal blood pressure reduction was observed in rats receiving kallikrein gene delivery compared with control rats receiving Ad.CMV-LacZ (160±5 versus 186±7 mm Hg, n=6, P <.01). The expression 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 and cardiomyocyte size, as well as an increase in renal blood flow, urine flow, glomerular filtration rates, electrolyte output, and urine excretion. Enhanced renal responses were accompanied by significant increases in urinary kinin, nitrite/nitrate, and cyclic GMP 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.