Muscle Delivery of Human Kallikrein Gene Reduces Blood Pressure in Hypertensive Rats

Abstract

We recently found that transgenic mice expressing human tissue kallikrein develop sustained hypotension. The result suggests that a continuous supply of human tissue kallikrein could have a prolonged effect on blood pressure reduction. In the present study, we investigated the potential of using human tissue kallikrein for gene therapy by injecting a kallikrein gene construct into the skeletal muscle of spontaneously hypertensive rats. Expression of the human tissue kallikrein messenger RNA in spontaneously hypertensive rats was identified by reverse transcription-polymerase chain reaction with Southern blot. Human tissue kallikrein was detected in the injected animals by an enzyme-linked immunosorbent assay. Injection of the human kallikrein gene into spontaneously hypertensive rats caused a significant reduction of systemic blood pressure, ranging from 15 to 26 mm Hg, compared with the control group. The differences were significant 1 week after the injection and continued for more than 2 months. Blood pressure reduction could be reversed after the administration of the bradykinin antagonist Hoe 140. The results indicate that somatic delivery of the human tissue kallikrein gene induces a sustained reduction of systemic blood pressure in spontaneously hypertensive rats. The present study raises the possibility of applying kallikrein gene therapy to the treatment of human hypertensive diseases.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…In the kidney, bradykinin has natriuretic effects (Sharma, 2009;Katori and Majima, 2003). Inducing bradykinin formation in hypertensive models reduces blood pressure (Martorana et al, 1990;Xiong et al, 1995;Chao et al, 1998;Spillmann et al, 2002;Wang et al, 2004). Thus, besides reducing angiotensin II production, ACE inhibitors may contribute to the control of blood pressure by increasing the concentration of bradykinin.…”

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Other mechanisms of endothelialdependent vasorelaxation are also suspected, such as the activation of a number of NO-independent ion channels located in the smooth muscle cells that may account for "endothelium-dependent hyperpolarization" (see application to the BK-induced relaxation of human isolated coronary microarteries; Batenburg et al, 2004). The physiological correlate of the vasodilator effect of kinins is hypotension when BK is administered systemically or when kinin formation is artificially promoted in a massive manner, as in hypertensive animals treated with a vector for activated tissue kallikrein (Xiong et al, 1995) or following activation of the contact system with intravenous dextran sulfate (Sabourin et al, 2001). Transgenic mice overexpressing the human B 2 receptor are also hypotensive and hyper-responsive to exogenous BK (Wang et al, 1997).…”

Recombinant adeno-associated virus-mediated kallikrein gene therapy reduces hypertension and attenuates its cardiovascular injuries

“…The procedures for ELISA analysis of HK in animal urine samples were performed according to the method described previously. 35,36 Purified rabbit antihuman tissue kallikrein IgG was dialyzed against 0.1 mol/l sodium bicarbonate buffer, pH 9.5, at 41C for 24 h and added to 10 ml freshly prepared 0.1 mol/l biotinyl-N-hydroxysuccinimide ester (dissolved in dimethyl formamide). The reaction was carried out at room temperature for 1 h, and the mixture was dialyzed against PBS.…”