Chao J, Chao L
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA.
Hypertension. 1996 Mar;27(3 Pt 2):491-4. doi: 10.1161/01.hyp.27.3.491.
Clinical studies show that an inverse correlation exists between blood pressure and urinary kallikrein levels. It has been postulated that the tissue kallikrein-kinin system contributes to the maintenance of normal blood pressure. To test this hypothesis, we have established transgenic mice that overexpress human tissue kallikrein under the promoter control of the mouse metallothionein gene and a liver-targeted albumin gene. These animals secrete human tissue kallikrein in plasma at levels 10- to 40-fold higher than that found in normal human serum, and they are chronically hypotensive. This hypotensive effect can be reversed by the injection of aprotinin, a potent tissue kallikrein inhibitor, or Hoe 140, a specific bradykinin receptor antagonist. Transgenic mice overexpressing human tissue kallikrein show a sustained reduction in blood pressure throughout their life spans, indicating the lack of sufficient compensatory mechanisms to reverse the hypotensive effect of kallikrein. Somatic gene delivery of rat kallikrein-binding protein by muscle injection increases the blood pressure of the hypotensive transgenic mice to levels comparable with those in normotensive control mice. These results indicate that a direct link exists between kallikrein gene expression and alterations in blood pressure. In addition, we have developed normotensive transgenic mice that harbor the human tissue kallikrein gene containing 801 bp of its native promoter. The tissue distribution pattern of human kallikrein in these transgenic mice is similar to that in human tissues, with the highest level in the pancreas and much lower levels in the kidney and salivary gland. These transgenic mice provide new animal models for investigating the tissue-specific regulation of tissue kallikrein and its role in altering blood pressure.
临床研究表明，血压与尿激肽释放酶水平呈负相关。据推测，组织激肽释放酶 - 激肽系统有助于维持正常血压。为了验证这一假设，我们构建了转基因小鼠，这些小鼠在小鼠金属硫蛋白基因和肝脏靶向白蛋白基因的启动子控制下过度表达人组织激肽释放酶。这些动物血浆中分泌的人组织激肽释放酶水平比正常人血清中高出10至40倍，并且它们长期低血压。注射抑肽酶（一种有效的组织激肽释放酶抑制剂）或Hoe 140（一种特异性缓激肽受体拮抗剂）可逆转这种降压作用。过度表达人组织激肽释放酶的转基因小鼠在其整个生命周期内血压持续降低，这表明缺乏足够的代偿机制来逆转激肽释放酶的降压作用。通过肌肉注射进行大鼠激肽释放酶结合蛋白的体细胞基因递送可将低血压转基因小鼠的血压提高到与正常血压对照小鼠相当的水平。这些结果表明激肽释放酶基因表达与血压变化之间存在直接联系。此外，我们还培育了正常血压的转基因小鼠，它们携带含有801 bp天然启动子的人组织激肽释放酶基因。这些转基因小鼠中人激肽释放酶的组织分布模式与人类组织相似，胰腺中水平最高，肾脏和唾液腺中水平低得多。这些转基因小鼠为研究组织激肽释放酶的组织特异性调节及其在改变血压中的作用提供了新的动物模型。
