KALLIKREINS AND KININS IN HYPERTENSION

目的是确定组织激肽释放酶是否对 动物模型中高血压遗传形式的病理学，以及 最终，在人类身上。组织知识的重要进展 激肽释放酶及其基因家族、合成与调控、定位 和功能责任，以及高血压状态下的异常 都是在过去五年里制造的。组织激肽释放酶和组织激肽释放酶 它们的激肽产物在肾脏和肠道离子和水的运输中 正在被揭示，特别是在依赖钙的生电方面 氯化物分泌和ADH刺激的水流。组织的成分 激肽释放酶-激肽系统(S)存在于大脑中，并对 对心血管动态平衡很重要的刺激。演示了 血管壁中的激肽释放素样酶(S)提供了新的机遇 对一种被认为在血管调节中起作用的系统的研究 抵抗。 我们将使用新工具来探索监管、活动水平和角色 组织激肽释放酶及其产品在上述地点的 自发性高血压或Dahl大鼠。它们包括：激肽释放酶基因， 合成率、酶原和活性酶的测量； 发展和/或维持含有或 对激肽释放酶系统组件的响应；测量其他 系统成分(如激肽、激肽原、一种新的组织激肽释放酶结合 蛋白质)或对这些成分的生物物理和生化反应(例如， 离子通量、膜片钳通道行为、二十烷类化合物合成或 肌醇磷脂转化)；抗组织激肽释放酶的单抗 抑制或刺激酶的物质；激动素受体阻滞剂。 我们的具体目标是：1)比较组织激肽释放酶系统在基因 高血压模型及其对照；2)进一步解释 膜转运事件中的组织激肽释放酶和激动素 3)测定组织激肽释放酶 系统对高血压疾病的遗传形式有因果关系；4) 与提供不同服务的合作者一起追求这些目标 激肽释放酶基因表达和酶的研究进展 责任，以及激肽释放酶在糖尿病肾功能中的作用。

The objective is to determine whether tissue kallikreins contribute to the pathology of genetic forms of hypertension in animal models, and ultimately, in man. Important advances in knowledge about tissue kallikreins, their gene families, synthesis and regulation, localization and functional responsibilities, and abnormality in hypertensive states were made over the last five years. The role of tissue kallikreins and their kinin products in renal and intestinal ion and water transport is being revealed, especially in regard to calcium-dependent electrogenic chloride secretion and ADH-stimulated water flow. Components of tissue kallikrein-kinin system(s) are present in the brain and show responses to stimuli important to cardiovascular homeostasis. The demonstration of kallikrein-like enzyme(s) in the vascular wall presents a new opportunity for study of a system suggested to have a role in regulation of vascular resistance. We will use new tools to explore regulation, levels of activity, and roles of tissue kallikreins and their products in the above-mentioned sites in spontaneously hypertensive or Dahl rats. They include: kallikrein mRNA, synthesis rate, zymogen, and active enzyme measurements; the ability to develop and/or maintain primary cell cultures which either contain or are responsive to kallikrein system components; the ability to measure other system components (e.g., kinins, kininogen, a new tissue kallikrein binding protein) or biophysical and biochemical responses to such components (e.g., ion fluxes, channel behavior via patch clamping, eicosanoid synthesis or phosphoinositide turnover); monoclonal antibodies to tissue kallikreins which inhibit or stimulate the enzyme; and kinin receptor blockers. Our specific aims are: 1) to compare tissue kallikrein systems in genetic hypertensive models and their controls; 2) to further explain the roles of tissue kallikreins and kinins in membrane transporting events which relate to cardiovascular homeostasis; 3) to determine whether tissue kallikrein systems contribute causally to genetic forms of hypertensive disease; 4) to pursue these objectives in concert with collaborators who provide different perspectives through work on kallikrein gene expression and enzyme responsibilities, and the role of kallikreins in diabetic renal function.