The tubular and cardiovascular effects of angiotensin II combine to make it one of the most important effectors of body Na conservation and blood pressure maintenance. Control of renin secretion, the ratelimiting step in the formation of angiotensin II, is therefore of critical importance for extracellular fluid volume and blood pressure homeostasis. Among the many factors that can alter renin secretion, special attention has been paid to the role of prostaglandins (PGs) as paracrine mediators because plasma and secretion levels of renin correlate directly with PG production in many clinical and experimental conditions. Covariation of renin and PG production is the result of a complex interaction that has the structure of a positive feedback relationship. Initially it was found that angiotensin II as well as other Ca-liberating agents can augment the release of PGs into renal venous blood w1x. Numerous subsequent studies have confirmed that angiotensin II enhances PG production in vascular smooth muscle, endothelial, and mesangial cells. It has also been shown that this is the result of activation of phospholipases C and A2, and augmented arachidonate release w2x. In the intact kidney, angiotensin II-stimulation of PG production occurs mostly in the vascular space and is probably mediated by endothelial cyclooxygenase-1 (COX-1) as the isoform most prominently expressed in the cortical renal vasculature w3, 4x. However, it has recently been shown that angiotensin II also augments the expression of the second cyclooxygenase isoform cyclooxygenase-2 (COX-2) in vascular smooth muscle cells w5x. Vascular production of vasodilator PGs acts as an important buffer against the renal constrictor action of angiotensin II and other vasoconstrictor agents.

While angiotensin II can stimulate PG production, the converse relation was shown to hold true as well: the intrarenal infusion of the PG precursor arachidonic acid increased plasma renin activity and inhibition of PG-synthase prevented renin stimulation w6x. Stimulation of renin secretion by PGs, most clearly by PGI2 and PGE2, was confirmed in renal cortical tissue slices, isolated glomeruli, and isolated juxtaglomerular granular cells w7±9x. The effect of PGE2 on renin release and expression is likely to be mediated by EP4 receptors on granular cells and signalling through an increase in cytosolic cAMP w10x. The macula densa mechanism for control of renin release was established as the physiological context in which prostaglandins were demonstrated to interact with renin-producing cells w11x. Direct evidence for PG-dependence of low NaCl-stimulation of renin secretion was obtained in the isolated perfused JGA preparation w12x. Participation of PGs in other renin control pathways such as sympathetic and baroreceptor mechanisms is less well established or unlikely. The mechanisms responsible for PG-dependent renin release, and the reasons why the macula densa mechanism was affected predominantly were unclear.