RENIN-ANGIOTENSIN SYSTEM AND ALDOSTERONE REGULATION

本课题的目的是分析生理学和病理学。 肾素-血管紧张素系统的研究进展，包括AII对血管紧张素系统的影响 循环动态平衡、胎儿发育、垂体和性腺功能。 ALII介导钠离子刺激时醛固酮分泌的增加 限制，但该肽对肾上腺的作用依赖于 肾小球区对AII的敏感性。先前对大鼠的研究 已经证明肾上腺对AII的反应性依赖于营养 多肽的作用和其他调节剂的调节作用 如多巴胺、心钠素(ANF)和生长抑素(SRIF)。 阐明这些因素调节效应的机制 所有这些都需要对所有这些方面的作用机制有一个精确的了解。这个 AII的细胞效应包括钙动员和磷脂 营业额。在分离的大鼠肾上腺小球细胞中，AII被显示为 引起蛋白激酶C(PKC)的移位和激活。 旨在确定PKC在类固醇生成作用中的作用的研究 提供了两条证据表明PKC不调解 AII对醛固酮分泌的刺激作用。第一，资源枯竭 佛波酯延长孵育时间对内源性PKC无影响 All刺激的醛固酮反应。第二，醛固酮对 当PKC被最大限度地转运到膜上时，AII被增强 佛波酯。这些数据表明，参与了AII对PKC的激活 在这样的功能中，如细胞生长，而不是直接刺激 醛固酮分泌。 已经进行了进一步的研究来表征新的AII结合 在大鼠和小鼠胚胎中发现的位置。这些受体广泛存在于 分布于骨骼肌和结缔组织 胎儿生命的最后三分之一，在出生后一天减少80%。这个 AII在胎儿发育中的作用正在进行二次培养研究 从胎儿皮肤中提取的细胞。这些细胞具有成纤维细胞样 并含有丰富的AII受体。孵化 含有ALII的培养导致细胞内钙迅速增加和 磷酸肌醇的形成。突出的和短暂的表达 胎儿中功能性的AII受体提示AII在 宫内发育。

The purpose of this project is to analyze physiological and pathological aspects of the renin-angiotensin system, including the effects of AII in circulatory homeostasis, fetal development pituitary and gonadal function. AII mediates the increase in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomerulosa zone to AII. Previous studies in the rat have demonstrated that the adrenal responsiveness to AII depends on trophic effects of the peptide and the modulatory effect of other regulators such as dopamine, atrial natriuretic factor (ANF) and somatostatin (SRIF). Elucidation of the mechanisms by which these factors modulate the effects of AII required a precise knowledge of the mechanism of action of AII. The cellular effects of AII include calcium mobilization and phospholipid turnover. In isolated rat adrenal glomerulosa cells, AII was shown to cause translocation and presumably activation of protein kinase C (PKC). Studies directed to determine the role of PKC in the steroidogenic action of AII provided two lines of evidence indicating that PKC does not mediate the stimulation of aldosterone secretion by AII. First, depletion of endogenous PKC by prolonged incubation with phorbol esters had no effect on AII-stimulated aldosterone responses. Second, the aldosterone response to AII is potentiated when PKC is maximally translocated to the membrane by a phorbol ester. These data suggest that PKC activation by AII is involved in such functions as cell growth rather that the direct stimulation of aldosterone secretion. Further studies have been performed to characterize the novel AII binding sites found in the rat and mouse fetus. These receptors are widely distributed throughout skeletal muscle and connective tissue during the last third of fetal life and are reduced by 80% one day after birth. The role of AII in fetal development is under study in secondary cultures of cells prepared from fetal skin. These cells have fibroblast-like characteristics and contain abundant AII receptors. Incubation of the cultures with AII resulted in rapid increase in cytosolic calcium and inositol phosphate formation. The prominent and transient expression of functional AII receptors in the fetus suggest a role of AII during intrauterine development.