PHYSIOLOGICAL ACTIONS OF THE RENIN-ANGIOTENSIN SYSTEM

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The purpose of this project is to study physiological and pathological aspects of the renin-angiotensin system, with emphasis on its role on circulatory homeostasis and development. The expression of AII receptor subtypes, type-1 (AT1), including AT1a and AT1b, and type-2 (AT2) were studied during development in the mouse. While AT1a was present in the adrenal gland, kidney, liver, ovary, testes, adipose tissue, lung, heart and brain of adult mice, AT1b was found only in the adrenal, and very low levels in testes and brain. In contrast to the marked changes in expression of AT2 receptors during development, similar proportions of AT1a and AT1b in the different tissues were found in fetal and adult mice. Studies in the rat using binding autoradiography and in situ hybridization showed converse changes in the expression of AT1 and AT2 in the kidney during post-natal development. Abundant AT2 receptor expression in the metanephric mass and advancing tubules and ampule of the ureteric bud of the immature kidney, decreased gradually through day- 14, disappearing after completion of nephrogenesis. In contrast, AT1 expression was very low 2 days after birth and was confined to the cortex and juxtamedullary boundary. AT1 expression progressively increased in correspondence to newly developed glomeruli and extended from the juxtamedullary boundary to the whole extent of the outer medulla. The temporal pattern of expression of the receptor subtypes suggests that while AT2 are involved in cell proliferation and early differentiation, AT1 receptors have a dual role in nephron differentiation and later in renal function. Studies on the brain renin-AII system focused on the role of AII in the regulation of the hypothalamic-pituitary-adrenal axis and vasopressin secretion. In situ hybridization studies showed AT1 receptor mRNA in periventricular and parvicellular perikarya of the paraventricular nucleus of the hypothalamus (PVN). Autoradiographic studies showed AII binding in areas corresponding to the mRNA location, but in addition AII receptors were clearly present in afferent fibers to the magnocellular division of the PVN. At the cellular level, double labelling in situ hybridization showed that AT1 receptor mRNA was located in corticotropin releasing hormone (CRH) neurons, but not in vasopressin and oxytocin neurons. In addition, central administration of AII increased CRH mRNA, but not VP mRNA levels in the PVN. The data suggest that while AII stimulates VP release indirectly through modulation of afferent innervation, AII has a direct regulatory effect on the CRH neuron.