Gene Therapy in Hypertension: Adenovirus-Mediated Kallikrein Gene Delivery in Hypertensive Rats

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Abstract
Tissue kallikrein has been shown to play a role in blood pressure regulation, and abnormalities in the kallikrein-kinin system are considered to be a factor in the pathogenesis of hypertension. To elucidate the potential therapeutic effects of kallikrein gene delivery in hypertension, an adenoviral vector containing the human tissue kallikrein gene under the control of a cytomegalovirus promoter, Ad.CMV-cHK, was intravenously injected into spontaneously hypertensive rats (SHR). A single injection of Ad.CMV-cHK into SHR caused a sustained delay in the increase in blood pressure from day 2 to day 41 post injection, as compared to control rats receiving Ad.CMV-LacZ aenovirus. Adenovirus-mediated kallikrein gene delivery had no effect on the blood pressure of normotensive Wistar-Kyoto rats. Human tissue kallikrein mRNA was detected in the liver, kidney, spleen, adrenal gland, and aorta. Immunoreactive human tissue kallikrein can be detected in sera and urine of rats receiving kallikrein gene delivery. Human tissue kallikrein in rat serum was at the highest level 5 days post injection, and the level declined gradually. Urinary kinin and cGMP levels were significantly increased in rats receiving kallikrein gene delivery compared to Ad.CMV-LacZ control rats. These results show that adenovirus-mediated delivery of human tissue kallikrein results in high-efficiency expression and blood pressure reduction in SHR. Application of adenovirus-mediated systemic expression of the tissue kallikrein gene may provide a unique way of delivering the gene product into the vasculature and could have important therapeutic implications in treating hypertension. Adenovirus-mediated gene delivery of human tissue kallikrein via the tail vein resulted in high-efficiency human kallikrein expression and a prolonged delay in the increase of blood pressure in spontaneously hypertensive rats for 6 weeks. The major sites of recombinant human kallikrein synthesis are the liver and kidney from which the protein is secreted into the circulation and urine. Kallikrein gene delivery resulted in increased urinary kinin and cyclic GMP levels, consistent with the blood pressure reduction being mediated via kinin through a cGMP-dependent signal transduction pathway. This study provides significant insight for future therapeutic applications.