REGULATION OF AT1 AND AT2 RECEPTORS DURING ONTOGENY

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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.