Human tissue kallikrein induces hypotension in transgenic mice.

Abstract

We investigated the role of the kallikrein-kinin system in blood pressure control by developing transgenic mice overexpressing human tissue kallikrein. Two lines of transgenic mice carrying the human tissue kallikrein gene under the control of the mouse metallothionein metal-responsive promoter were established. Human tissue kallikrein was identified in pancreas, salivary gland, kidney, liver, and spleen of the transgenic 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 product were parallel with the human tissue kallikrein standard curve, indicating their immunologic identity. The expression of human tissue kallikrein transcript in the transgenic mice was further confirmed by Northern blot analysis and by reverse transcription-polymerase chain reaction followed by Southern blot. Both lines of transgenic mice had significantly 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 (10O.9±5.0 mm Hg, n=8). Induction with zinc did not lower the blood pressure further despite elevated expression of the transgene. Administration of aprotinin, a potent tissue kallikrein inhibitor, restored the blood pressure of the transgenic mice but had no significant effect on control littermates. 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. (Hypertension. 1994^3:236-243.)-

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

“…All standard cell culture reagents were obtained from Gibco BRL (Life Technologies, Inc., Grand Island, NY) including Dulbecco's sured weekly with a manometer-tachometer (Rat Tail NIBP System, ADI Instruments, Australia) by the tail-cuff method [21] immediately after injection until the experiments ended. At 25 weeks after gene delivery, all the animals were sacrificed (euthanasia), and the major organs including brain, heart, lungs, liver, and kidneys were collected, frozen in liquid nitrogen followed by storage in -80 o C for later morphology and gene expression analysis.…”

Molecular biology of the kallikrein-kinin system: from structure to function

“…Transgenic mice carrying the human kallikrein gene under the control of the mouse metallothionein metal-responsive promoter expressed the human protein in several organs and, similarly to the model overexpressing the B2 receptor (see below), displayed significantly lowered blood pressure compared to control mice (30). Transgene expression in the mice was checked by specific radioimmunoassay and ELISA for human tissue kallikrein.…”

Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients

“…Mice and rats overexpressing human tissue kallikrein gene are permanently hypotensive throughout their lifetime. 11 A single injection of human tissue kallikrein plasmid cDNA constructs into SHRs causes a prolonged reduction of systolic BP (SBP). The extent of BP reduction is dependent on the dose of injected DNA.…”