Objective To investigate the effect and mechanism of prostaglandin E2 (PGE2) in renin regulation at the juxtaglomerular apparatus (JGA). Methods Macula densa cell line (MMDD1) was cultured on the special filter. In the medium on the apical lateral of the cells, low concentration of sodium chloride, chloride and different doses of angiotensin Ⅱ(AngⅡ) were used to stimulate the PGE2 secretion. The PGE2 concentration was tested by ELISA. In the animal experiment, the response of plasma renin activity (PRA) to acute intraperitoneal administration of captopril (30 mg/kg) was determined, in conscious wild-type (WT) and cyclooxygenase COX-2－/－ mice on C57BL/6 genetic backgrounds. PRA was measured in plasma obtained by tail vein puncture. Different concentrations of PGE2 were used to stimulate the renin secretion of primary cultured JGA cells from COX-2－/－ mice and wild type mice. In specific Gsα gene delete mice (low renin producing mice), 24 h urine was collected to test the concentration of PGE2. The COX-2 mRNA and protein of the kidney cortex were observed by real-time PCR and immunohistochemical staining. Results Low chloride could stimulate the PGE2 secretion both at the apical and basement of the macula densa cells. In COX-2－/－ mice, the base PRA and [(378.3±96.4) vs(1115.0±210.0) ng AngI•ml-1•h-1，P＝0.0051，n＝10] the renin secretion of primary cultured JGA cells [(153.7±14.7) vs (672.4±129.0) ng AngI•ml-1•h-1，P＝0.0162，n＝3] were obviously lower than wild type mice. Captopril could stimulate the PRA of (COX)-2－/－ mice increasing 32.8 times. But AngⅡ had no effect on PGE2 secretion in macula densa cells. In primary cultured JGA cells, the decreasing renin scretion was partly recovered by PGE2 in cells from COX-2－/－ mice. In low renin producing mice, the expression of COX-2 mRNA in the kidney cortex increased by (8.07±1.08) times(n=6, P=0.0022). The COX-2 protein of the kidney cortex and the urine PGE2 increased by several times. Conclusions Low chloride is the primary stimulation messenger of PGE2 secretion in macula densa cells. The PRA in COX-2－/－ mice can be stimulated by angiotensin converting enzyme inhibitor, but the AngⅡ has no direct effect on macula densa cells. When renin production is abolished in JGA cells (Gsα delete mice), COX-2 mRNA and protein up-regulation is observed in kidney cortex and macula densa. PGE2 plays an important role in regulation of renin secretion and renin release in JGA by precise feedback mechanism.