PARACRINE REGULATION OF THE RENAL MICROCIRCULATION

组织激肽释放酶-激肽系统已经涉及到调节 肾功能、血流量（BF）和血压（BP）， 高血压的发病机制 我们提供的证据表明， 主要作为调节肾功能的局部激素（自体激素） 急性肾血流动力学、利钠利尿作用 血管紧张素转换酶抑制剂（ACE）。 在这里，我们建议测试 内源性激肽调节肾功能（GFR， 总BF和乳头BF）通过EDRF和类二十烷酸，并且它们作用于 与ANF协同调节水和钠排泄，特别是在 涉及高肾激肽和/或内源性ANF的情况。 通过 在这些机制中，激肽在肾脏的慢性调节中发挥作用。 功能，作为利尿钠和利尿激素。 具体地说， 我们提出：I）确定a）肾中的激肽是否作用于B1 和/或B2受体; B）内源性激肽是否作用于细胞膜上的受体， 肾单位的基底外侧和/或管腔侧;以及c）鉴定肾单位的基底外侧和/或管腔侧。 在显微切割的肾单位中B2激肽受体的表达位点; II）在体内确定内源性激肽对肾功能的影响， 功能部分由EDRF和PG介导，以及它们的一部分是否 作用被EDCF（PG-内过氧化物和血栓素，TxA 2）拮抗。 III）进一步推进激肽和ANF作用于 协同地。 他们对钠通量的影响将在隔离的 灌注的皮质集合管。 我们有证据表明激肽 与ANF协同作用，抑制ISC和PD对皮质收集的影响 细胞培养。 我们建议研究激肽和 ANF协同作用以减少转运; IV）在体内研究是否 在激肽和内源性ANF之间存在相互作用。 为 为此，我们将确定阻断激肽和/或ANF的作用。 （单克隆抗体）：a）水和钠排泄，B）肾 皮质和乳头BF，和c）肾间质压。 我们将 研究刺激内源性ANF释放的情况，例如 在正常和DOCA-盐大鼠中的体积扩张;和V）确定是否 激肽受体的慢性阻断改变肾功能（GFR，肾BF， 蛋白尿和水和钠排泄）的高蛋白饮食大鼠 以及用激肽酶抑制剂治疗的肾病综合征大鼠。

The tissue kallikrein-kinin system has been implicated in the regulation of renal function, blood flow (BF) and blood pressure (BP) and in the pathogenesis of hypertension. We have provided evidence that kinins act mainly as local hormones (autacoids) in the regulation of renal function and in the acute renal hemodynamic, natriuretic and diuretic effects of angiotensin-converting enzyme inhibitors (ACE). Here we propose to test the general hypothesis that endogenous kinins regulate renal function (GFR, total and papillary BF) via EDRF and eicosanoids, and that they act in synergism with ANF to regulate water and sodium excretion, especially in situations involving high renal kinins and/or ANF of endogenous origin. By these mechanisms, kinins play a role in the chronic regulation of renal function, acting as both natriuretic and diuretic hormones. Specifically, we propose: I) to determine a) whether kinins in the kidney act on B1 and/or B2 receptors; b) whether endogenous kinins act on receptors on the basolateral and/or luminal sides of the nephron; and c) to identify the site of expression of the B2 kinin receptor in the microdissected nephron; II) to determine in vivo whether the effects of endogenous kinins on renal function are mediated in part by EDRF and PGs, and whether part of their effects are antagonized by EDCFs (PG-endoperoxide and thromboxane, TxA2). III) to further advance the hypothesis that kinins and ANF act synergistically. Their effects on sodium flux will be tested in isolated perfused cortical collecting ducts. We have evidence that kinins act synergistically with ANF, inhibiting ISC and PD on cortical collecting cells in culture. We propose to study the mechanism(s) by which kinins and ANF act synergistically to decrease transport; IV) to study in vivo whether there is an interaction between kinins and ANF of endogenous origin. For this, we will determine the effect of blocking kinins and/or ANF (monoclonal antibodies) on: a) water and sodium excretion, b) renal cortical and papillary BF, and c) renal interstitial pressure. We will study situations in which endogenous ANF release is stimulated, such as volume expansion in normal and DOCA-salt rats; and V) to determine whether chronic blockade of kinin receptors alters renal function (GFR, renal BF, proteinuria and water and sodium excretion) in rats fed high protein diets and in rats with nephrotic syndrome treated with kininase inhibitors.