The cellular machanisms involved in the biochemistry and physiology of snythesis and secretion of renin are the key events in the primary control of renin-angiotensinaldosterone system. We propose an indepth study of the role of calcium in renin release. Calcium is an essential component in vascular smooth muscle function. An increase in cytosolic calcium is associated with constriction and a decrease in vasodilation. Renin secreting cells are derived from vascular smooth muscle cells and existing studies suggest that a rise in calcium suppresses while a decrease in calcium stimulates renin release. This is in contrast to the usual theme of calcium linked secretion in many other systems. Specifically we will focus on 1) whether atrial natriuretic factor (atriopeptins) from the cardiac atria acts not only to suppress aldosterone secretion but whether this new hormone suppresses renin secretion. Peliminary data suggests this. Also, whether this hormone acts through Ca++ in its action, 2) whether an important agonist prostacyclin (PGI2) induces secretion of renin by calcium, and 3) we will study if prostaglandins are the physiological mediators in the conversion of pro or inactive renin to active renin via calcium. We have preliminary data in man that prostaglandins are involved in this step of conversion of inactive to active renin. In vitro studies using rat and rabbit renal cortical slices will be used to study the release of active (rat and rabbit) and inactive (rabbit) renin under various alterations of calcium flux. The approaches will include effects of altering extracellular calcium alone and in the presence of atriopeptins (I, II, III and IV) as well as prostaglandins (PGI2, PGE2, 6 keto E1). Cellular levels of calcium will be increased by use of a series of ionophores. The role of extracellular calcium can be explored by the use of entry inhibitors (verapamil, nifedipine and diltiazem). Calcium acts in large part by binding to calmodulin which then by confirmational change induces protein phosphorylation. Inhibitors such as TFP, calmidazolium and TMB8 can be utilized to probe whether Ca-calmodulin is involved in renin secretion, and in the rabbit activation of inactive-active renin conversion and release. These studies should reveal if physiological mediators (such as atriopeptins as well as prostaglandins) cause the sequential changes in renin in juxtaglomerular cells of the kidney via intra or extracellular calcium or by activation of calcium-calmodulin system and if calcium ions or calmodulin play a role in prostaglandin's conversion of inactive to active renin.
