HUMAN TISSUE KALLIKREIN INDUCES HYPOTENSION IN TRANSGENIC MICE

We investigated the role of the kallikrein-kinin system in blood press ure control by developing transgenic mice overexpressing human tissue kallikrein. Two lines of transgenic mice carrying the human tissue kal likrein gene under the control of the mouse metallothionein metal-resp onsive promoter were established. Human tissue kallikrein was identifi ed in pancreas, salivary gland, kidney, liver, and spleen of the trans genic mice by a specific radioimmunoassay for human tissue kallikrein. The immunoreactive human tissue kallikrein reached high levels in the circulation. The linear displacement curves for the transgenic produc t were parallel with the human tissue kallikrein standard curve, indic ating their immunologic identity. The expression of human tissue kalli krein transcript in the transgenic mice was further confirmed by North ern blot analysis and by reverse transcription-polymerase chain reacti on followed by Southern blot. Both lines of transgenic mice had signif icantly lowered blood pressure (86.4+/-13.5 mm Hg [mean+/-SD], n=8 and 78.9+/-12.4 mm Hg, n=8) compared with control mice (100.9+/-5.0 mm Hg , n=8). Induction with zinc did not lower the blood pressure further d espite elevated expression of the transgene. Administration of aprotin in, a potent tissue kallikrein inhibitor, restored the blood pressure of the transgenic mice but had no significant effect on control litter -mates. Our findings raise the possibility of tissue kallikrein being a powerful modulator of blood pressure and provide a new animal model for the study of blood pressure regulation.