Human Kallikrein Gene Delivery Attenuates Hypertension, Cardiac Hypertrophy, and Renal Injury in Dahl Salt-Sensitive Rats

Abstract

The tissue kallikrein-kinin system has been documented to be involved in the pathogenesis of hypertension and renal diseases. To investigate the protective effects of kallikrein gene delivery on salt-induced renal damage, cardiac dysfunction, and hypertension, adenovirus harboring the human tissue kallikrein gene under the control of the cytomegalovirus promoter Ad.CMV-cHK was delivered into Dahl salt-sensitive (Dahl-SS) rats fed to a high-salt (4% NaCl) diet. A single intravenous injection of Ad.CMV-cHK resulted in a significant reduction of blood pressure beginning 2 days post injection and the effect lasted for 4 weeks. The human kallikrein mRNA was detected in rat heart, kidney, lung, liver, and adrenal gland; immunoreactive human kallikrein can be measured in the liver, kidney, sera, and urine of rats receiving kallikrein gene delivery. Following Ad.CMV-cHK injection, a significant increase in urine excretion, urinary sodium output, kinin, and cGMP level was observed. Kallikrein gene delivery caused a significant reduction in the left ventricular mass and cardiomyocyte size as well as inhibition of glomerular sclerotic lesions and tubular dilatation. This study shows that adenovirus-mediated gene delivery in Dahl-SS rats fed a high-salt diet resulted in (i) prolonged reduction of blood pressure and increased urinary kinin and cGMP levels, consistent with blood pressure reductions mediated via kinin through a cGMP-dependent signal transduction pathway, (ii) inhibition of cardiac hypertrophy, and (iii) attenuation of renal injury. The ability of kallikrein gene transfer 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.