The renin-angiotensin system plays a major role in the regulation of blood pressure and electrolyte homeostasis in mammals. In this study, we subjected transgenic mice containing a human renin genomic construct to a variety of pharmacological and physiological manipulations to test whether expression of the human renin gene and release of active human renin in appropriately regulated in this model. These manipulations were designed to test major regulators of renin release, including angiotensin II, the macula densa, renal perfusion pressure, and beta-adrenergic receptors. We used human plasma renin concentration and human renal renin mRNA levels to document the response of the transgene to these stimuli. Human plasma renin concentration increased in response to both angiotensin-converting enzyme inhibition with captopril and isoproterenol and decreased after a high salt diet. A low salt or sodium-deficient diet did not stimulate renin release. Human renin mRNA levels in kidney increased after captopril but were unchanged in the other experimental groups. We also measured the levels of human renin mRNA in double transgenic mice containing the same human renin gene in addition to the human angiotensinogen gene. These mice are chronically hypertensive and have increased circulating levels of angiotensin II. Human renin mRNA levels in the kidney were paradoxically elevated compared with their single transgenic normotensive counterparts. These transgenic mice provide a model for examination of human renin regulation and may help elucidate the molecular mechanisms that regulate the gene in response to physiological cues.