PARACRINE REGULATION OF THE RENAL MICROCIRCULATION

组织激肽释放酶-激肽释放酶系统参与了 肾功能、血流量(BF)和血压(BP) 高血压的发病机制。我们已经提供了激肽起作用的证据 主要作为局部激素(类耳石)调节肾功能 并在急性肾血流动力学、利钠和利尿作用方面 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， 全脂和乳头状BF)通过EDRF和二十烷类化合物，它们作用于 与ANF协同调节水和钠的排泄，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，激动素在肾脏的慢性调节中发挥作用 功能，同时作为利钠和利尿荷尔蒙。具体来说， 我们建议：i)确定a)肾脏中的激动素是否作用于B1 和/或B2受体；b)内源性激肽是否作用于 肾单位的基底外侧和/或腔内侧；以及c)识别 B2激动素受体在显微解剖肾单位的表达部位； 二)在体内确定内源性激肽对肾脏的影响 功能部分是由EDRF和PG介导的，而它们的部分 这种作用可被内源性过氧化氢和血栓素A_2拮抗。 三)进一步提出激动素和心钠素起作用的假设 协同作用。它们对钠通量的影响将在隔离的 灌流的皮质集合管。我们有证据表明激肽能起作用 与ANF协同抑制ISC和PD的皮质收集 培养中的细胞。我们建议研究(S)激动素和 ANF协同作用减少转运；IV)体内研究 激肽与内源性ANF之间存在相互作用。为 为此，我们将确定阻断激动素和/或心钠素的效果 (单抗)：a)水和钠的排泄，b)肾脏 皮质和乳头状血流量，以及c)肾间质压力。我们会 研究刺激内源性心钠素释放的情况，例如 正常大鼠和DOCA-盐大鼠的体积扩张；以及V)确定 慢性阻断激动素受体改变肾功能(GFR，肾BF， 高蛋白饮食大鼠的蛋白尿和水钠排泄 在使用激肽酶抑制剂治疗肾病综合征的大鼠中也是如此。

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.