REGULATION OF AT1 AND AT2 RECEPTORS DURING ONTOGENY

我们目前对AT 1和AT 2受体在肿瘤发生过程中的作用的理解， 发展基本上来自体外进行的研究（1-4）。 据我们所知，还没有体内研究表明， 研究了AT 1或AT 2受体在 心血管和肾脏功能在胎儿发育过程中。的 肾组织中AT 1和AT 2受体的差异表达 （见初步数据）表明，生理作用 所有的变化。 根据这些研究，我们 假设肾脏对AT 1和AT 2的生理反应 受体激活在胎儿期依赖于发育 AT 1的解剖分布和表达水平的变化 和AT 2受体以及成熟的信号转导机制 调节对AT 1和AT 2受体活化的细胞应答。 为了检验这一假设，本提案旨在：（a） 阐明AT 1和AT 2的生理作用和分子调控 （B）确定以下因素对绵羊胎儿期受体的影响： 信号转导机制的成熟变化（cAMP， 磷脂酶C、cCMP和磷酸酪氨酸磷酸酶）对 对AT 1和AT 2受体活化的生理性肾反应;和 (c)阐明AT 1在体内和体外的各自作用， 和AT 2受体对原癌基因（c-fos，c-myc， n-myc）和生长相关基因（TGF-α、TGF-β、IGF-I和IGF-II） 在胎儿肾脏发育的不同时期。 这些研究将 首次阐明了调控表达的机制， 胎儿肾发育过程中AT 1和AT 2受体的生理活性 发展 了解这些机制对于 确定和防止潜在的胎儿有害影响，这些新的 血管紧张素II受体拮抗剂用于孕妇和 早产儿和足月新生儿。

Our present understanding of the role of AT1 and AT2 receptors during development comes essentially from studies performed in vitro (1-4). To our knowledge, there have been no studies in vivo that have investigated the physiological role of AT1 or AT2 receptors on cardiovascular and renal functions during fetal development. The differential expression of AT1 and AT2 receptors during kidney development, (see preliminary data) suggest that the physiological role of AII changes during development. Based on these previous studies we are postulating that the physiological renal responses to AT1 and AT2 receptor activation during fetal life are dependent on the developmental changes in the anatomical distribution and levels of expression of AT1 and AT2 receptor and on the maturation of signal transduction mechanisms regulating the cellular responses to AT1 and AT2 receptor activation. To test this hypothesis, the present proposal is designed (a) to elucidate the physiological role and molecular regulation of AT1 and AT2 receptors during fetal life in sheep; (b) to determine the influence of maturational changes in signal transduction mechanisms (cAMP, phospholipase C, cCMP, and phosphotyrosine phosphatase) on the physiological renal responses to AT1 and AT2 receptor activation; and (c) to elucidate both in vivo and in vitro the respective role of AT1 and AT2 receptors on the regulation of proto-oncogenes (c-fos, c-myc, n-myc) and growth related genes (TGF-alpha, TGF-beta, IGF-I and IGF-II) at different times during fetal renal development. These studies will elucidate for the first time the mechanisms regulating the expression and physiological activity of AT1 and AT2 receptors during fetal renal development. Understanding of these mechanisms is essential to determine and to prevent potential fetal harmful effects of these new angiotensin II receptor antagonists when used in pregnant women and in preterm and term newborn infants.