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 other factors which modulate the sensitivity of the glomerulosa zone to AII. A novel finding was that serotonin, a known direct stimulator of aldosterone secretion has marked potentiating effect on the steroidogenic actions of AII. In contrast with the direct stimulatory effect of 5HT on aldosterone production which is mediated by cAMP, the enhancement of the effect of AII is due to potentiation of AII induced increases in cytosolic calcium. The interaction between a AMP dependent and independent mechanisms in the regulation of aldosterone secretion was further studied in isolated adrenal glomerulosa cells. Activation of protein kinase C (PKC) by preincubation of the cells with phorbolesters (PBE) results in about 30% decrease in ACTH stimulated aldosterone and cAMP production, while PKC inhibition caused enhancement of the ACTH responses. In contrast to the effect of PBE preincubation simultaneous addition of ACTH and PBE resulted in potentiation of the ACTH response. The data demonstrates that the modulatory effects of PKC on steroidogenesis is dependent on receptor occupancy, and may be important in the control of the adrenal responsiveness to regulators. Studies on the central activity of AII were extended to the analysis of brain AII receptors during development. Receptors were present in areas related with water intake and control of blood pressure at all ages. In addition there were dynamic changes in a number of brain areas suggesting that AII has a role in neuronal maturation during development. A new observation was the demonstration of abundant AII receptors in skeletal muscle and connective tissue of monkey and human fetus, suggesting a role for AII in fetal development in primates. The effects of AII on cellular growth were studied in cultured mesangial cells. AII receptors were present in cultured fetal and adult mesangial cells and incubation of the cells with AII resulted in stimulation of thymidine incorporation and cell division. The data suggests a role for AII in the proliferative response during glomerular disease.
