The human renin gene is expressed in the kidney, placenta, and several other sites. The release of renin or its precursor, prorenin, can be affected by several regulatory agents. In this study, primary cultures of human placental cells were used to examine the regulation of prorenin release and renin mRNA levels and of the transfected human renin promoter linked to chloramphenicol acetyltransferase reporter sequences. Treatment of the cultures with a calcium ionophore alone, calcium ionophore plus forskolin (that activates adenylate cyclase), or forskolin plus a phorbol ester increased prorenin release and renin mRNA levels 1.3-to 6-fold, but several classes of steroids did not affect prorenin secretion or renin RNA levels. The transfected renin promoter (584 or 100 base pairs of 5'-flanking DNA) initiated at the correct start site in these cells and forskolin increased its expression 2.5-to 4-fold. Constructs containing renin 5'-flanking DNA linked to a heterologous promoter cotransfected into HeLa cells with either glucocorticoid or estrogen receptor expression vectors were not regulated by dexamethasone or 17fi-estradiol. These results suggest that (i) the first 584 base pairs of the renin gene 5'-flanking DNA do not contain functional glucocorticoid or estrogen response elements, (i) placental prorenin release and renin mRNA are regulated by calcium ion and by the combinations of cAMP with either C kinase or calcium ion, and (iii) the first 100 base pairs of the human renin 5'-flanking DNA direct accurate initiation of transcription and ean be regulated by cAMP. Thus, some control of renin release in the placenta (and by inference in other tissues) occurs via transcriptional influences on its promoter.amine hormones, such as cAMP (activated by forskolin; refs. 10 and 11), calcium ion, C kinase (activated by phorbol esters; ref. 12), and steroid hormones (13). Several stimuli that activate adenylate cyclase affect renin or prorenin release: P-adrenergic stimuli enhance renal renin release (2, 14); chorionic gonadotropin and luteinizing hormone increase plasma prorenin levels (15, 16); and forskolin increases prorenin release from placental preparations (5). Angiotensin II inhibits renal renin release and its actions may be mediated by calcium ion and protein kinase C (2, 17-19). Estrogens can increase plasma renin levels (20) and may stimulate prorenin release from the human ovary (15, 21). Mineralocorticoid hormones block renin release through their salt-retaining actions (2). The renin gene 5'-flanking DNA contains sequences that have some homology to estrogen and glucocorticoid response elements (22), but it is unclear whether any of these steroids affect renin gene transcription.In the current studies, human chorion cell primary cultures have been used to study the control of both the endogenous renin gene and of transfected genes containing human renin gene 5'-flanking DNA. The results show that endogehous renin gene expression can be regulated by calcium ion alone or with forskolin, and forskoli...