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. Studies in neonatal rats showing decreased aldosterone responses to angiotensin II (AII) associated to the presence of abundant adrenal AT2 receptors suggested developmental changes in the regulation of the adrenal glomerulosa function. In collagenase dispersed adrenal glomerulosa cells from 7-day old rats, blockade of AT2 receptors had no effect on the stimulation of aldosterone production by AII, indicating that AT2 receptors are not involved in the steroidogenic actions of AII. An important finding was that in contrast to adult rats, plasma aldosterone levels stimulated by AII and ACTH and the last step of the aldosterone biosynthetic pathway, aldosterone synthetase, were markedly inhibited by administration of dexamethasone 18 hr earlier. Preincubation of isolated adrenal cells with dexamethasone for 2 hr had no effect on basal or stimulated aldosterone production. The inhibitory effect in vivo, was not prevented by ACTH suggesting that in neonatal rats aldosterone secretion is under the influence of a glucocorticoid sensitive factor different from ACTH. Continuation of studies on the effects of AII in human kidney mesangial cells revealed that incubation of confluent cell cultures with AII caused significant increases in fibronectin mRNA level and fibronectin synthesis. The stimulatory effect of AII in the expression of extracellular matrix proteins suggest the involvement of AII in the pathogenesis of glomerular disease. The role of AII receptor changes in the altered vascular responsiveness to AII in portal hypertension was studied in a surgical model of portal hypertension in the rabbit. AII receptor content was significantly decreased in vascular smooth muscle membranes from mesenteric artery and portal vein of portal hypertensive rabbits. This may explain the blunted pressor responses to AII observed in portal hypertension. The topographic distribution of AII receptor mRNA was studied in the rat brain using cRNA probes obtained by PCR using primers based on the sequence of AT1 receptor and cDNA from rat brain. AT1 receptor mRNA was located in ares known to contain AT1 receptor binding. In addition, expression of AT1 receptor mRNA in areas in which binding has not been shown, such as the hippocampus and arcuate nucleus indicate that the presence of low levels of receptors may explain the reported biological effects of AII in these areas.