Homeostatic Response of Mouse Gene Transcription in a Hypertensive Environment Is Mediated by a Novel 5' Enhancer.

The renin-angiotensin system plays an essential role in blood pressure homeostasis. Because renin activity is reflected as a blood pressure phenotype, its gene expression in the kidney is tightly regulated by a feedback mechanism; i.e., gene transcription is suppressed in a hypertensive state. To address the molecular mechanisms controlling hypertension-responsive mouse (m) gene regulation, we deleted either 5' (17-kb) or 3' (78-kb) regions of the endogenous m gene and placed the animals in a hypertensive environment. While the m gene bearing the 3' deletion was appropriately downregulated, the one bearing the 5' deletion lost this hypertension responsiveness. Because the 17-kb sequence exhibited enhancer activity and , we narrowed down the enhancer to a 2.3-kb core using luciferase assays in As4.1 cells. When this 2.3-kb sequence was removed from the endogenous m gene in the mouse, its basal expression was dramatically reduced, and the hypertension responsiveness was significantly attenuated. Furthermore, we demonstrated that the angiotensin II signal played an important role in m gene suppression. We propose that in a hypertensive environment, the activity of this novel enhancer is attenuated, and, as a consequence, m gene transcription is suppressed to maintain blood pressure.