High Level of Circulating Human Tissue Kallikrein Induces Hypotension in a Transgenic Mouse Model

Abstract

We established a unique transgenic mouse model with liver-targeted expression of human tissue kallikrein using a mouse albumin enhancer and promoter. Northern blot analysis and ELISA showed that human tissue kallikrein was predominantly expressed in the liver of transgenic mice and secreted into the circulation at a high level. The transcript was also detected in the kidney, pancreas, salivary gland and heart at a low level by reverse transcription-polymerase chain reaction followed by Southern blot analysis. Systolic blood pressures were measured by the tail-cuff method, all three inde endent transgenic 83.1f0.8 mmHg, n = 13, P < 0.01) compared with the control mice (100. 9kO. 9 mmHg, n = 17). Administration of aprotinin, a potent tissue kallikrein inhibitor or Hoe 140, a bradykinin receptor antagonist, restored the blood pressure of transgenic mice but had no significant effect on control littermates. These studies show that over-production of tissue kallikrein in the circulation plays a role in blood pressure regulation. Mouse lines are hypotensive (84.6k1.0 mmHg, n = 17; 84.5-1.5 P mmHg, n = 9;83.1f0.8 mmHg, n = 13, P c 0.01) compared with the control mice (100. 9kO. 9 mm Hg, n = 17). Administration of aprotinin, a potent tissue kallikrein inhibitor or Hoe 140, a bradykinin receptor antagonist, restored the blood pressure of transgenic mice but had no significant effect on control littermates. These studies show that over-production of tissue kallikrein in the circulation plays a role in blood pressure regulation.

Key Words:

• human tissue kallikrein
• transgenic mice
• hypotension
• albumin promoter
• Hoe 140
• aprotinin