cAMP/PKA signaling is the central intracellular mechanism that controls the expression of renin gene. In vitro studies have demonstrated that cAMP targets cAMP Response Elements (CRE) in the renin gene promoter. Therefore we aimed to investigate the functional role of the human renin promoter CRE sequences in vivo. Two functional CRE sites were identified in the human renin promoter: proximal promoter CNRE (cAMP and overlapping negative response element) and distal enhancer CRE. Therefore we generated transgenic mice expressing lacZ reporter under the control the human renin promoter containing mutations in enhancer CRE and proximal CNRE. Beta-gal staining for lacZ of adult mouse kidneys showed that the transgene is correctly targeted to the juxtaglomerular (JG) portion of the afferent arterioles which expresses endogenous renin. In addition, weak beta-gal reaction was observed in larger renal arteries, in glomeruli as well as in medullary collecting ducts and interstitial cells. Chronic treatment of the transgenic mice with an angiotensin converting enzyme (ACE) inhibitor (Enalapril 10 mg/kg/d for 7 days) stimulated the expression of both endogenous renin and the lacZ reporter. Immunohistochemical co-staining for renin and lacZ demonstrated recruitment of additional renin/lacZ positive cells in the afferent arterioles of Enalapril-treated animals. Similar transgene expression was observed in angiotensin receptor 1a knockout mice when crossed with the lacZ strain. On the other hand renin expression was up-regulated by a low-salt diet (0.03% NaCl for 10 days), while lacZ expression tended to decrease. Our data suggest that the cAMP-targeted regulatory sequences are dispensable for the cell-specific expression and for the regulation by angiotensin, but are necessary for the salt-dependent stimulation of human renin gene.