Dietary protein restriction inhibits glomerular prostaglandin (PG) synthesis and lowers plasma renin activity (PRA). To investigate the role of PG in mediating protein-induced alterations in renin secretion, male Sprague-Dawley rats were fed isocaloric diets providing either a standard 20% protein or a low-protein (6%) diet for 3 wk. An additional group of rats received a PG synthesis inhibitor, meclofenamate (25 mg/l), in the drinking water along with the 20% protein diet. Both protein restriction and meclofenamate administration significantly (P less than 0.025) lowered glomerular PGE2 production. Compared with standard protein intake, low protein intake lowered basal PRA (3.96 +/- 0.16 vs. 1.58 +/- 0.12 ng.ml-1.h-1, P less than 0.001), stimulated PRA (11.6 +/- 2.3 vs. 5.5 +/- 0.7 ng.ml-1.h-1, P less than 0.025), renal venous PRA (10.0 +/- 0.7 vs. 7.02 +/- 0.72 ng.ml-1.h-1, P less than 0.02), and plasma angiotensin II (ANG II) levels (52 +/- 5 vs. 24 +/- 3 pg/ml, P less than 0.01), while augmenting renal tissue renin content (2.36 +/- 0.21 vs. 3.56 +/- 0.30 micrograms/mg protein, P less than 0.005). Changes in plasma and renal tissue renin on meclofenamate treatment were similar to those observed on 6% protein diet. Both protein restriction and meclofenamate administration increased the glomerular ANG II receptor number, while the receptor affinity was unchanged. Thus protein restriction lowers PRA by impairing release of renin into circulation. This impairment in renin release is mediated by PG.