TY - JOUR
T1 - Homeostatic response of mouse renin gene transcription in a hypertensive environment is mediated by a novel 5' enhancer
AU - Ushiki, Aki
AU - Matsuzaki, Hitomi
AU - Fukamizu, Akiyoshi
AU - Tanimoto, Keiji
N1 - Publisher Copyright:
© 2018 American Society for Microbiology.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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., renin gene transcription is suppressed in a hypertensive state. To address the molecular mechanisms controlling hypertension-responsive mouse renin (mRen) gene regulation, we deleted either 5' (17-kb) or 3' (78-kb) regions of the endogenous mRen gene and placed the animals in a hypertensive environment. While the mRen 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 in vivo and in vitro, 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 mRen 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 mRen gene suppression. We propose that in a hypertensive environment, the activity of this novel enhancer is attenuated, and, as a consequence, mRen gene transcription is suppressed to maintain blood pressure.
AB - 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., renin gene transcription is suppressed in a hypertensive state. To address the molecular mechanisms controlling hypertension-responsive mouse renin (mRen) gene regulation, we deleted either 5' (17-kb) or 3' (78-kb) regions of the endogenous mRen gene and placed the animals in a hypertensive environment. While the mRen 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 in vivo and in vitro, 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 mRen 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 mRen gene suppression. We propose that in a hypertensive environment, the activity of this novel enhancer is attenuated, and, as a consequence, mRen gene transcription is suppressed to maintain blood pressure.
KW - Enhancer
KW - Genome editing
KW - Homeostasis
KW - Hypertension
KW - Renin angiotensin system
KW - Transcription
UR - http://www.scopus.com/inward/record.url?scp=85043974561&partnerID=8YFLogxK
U2 - 10.1128/MCB.00566-17
DO - 10.1128/MCB.00566-17
M3 - Article
C2 - 29358217
AN - SCOPUS:85043974561
SN - 0270-7306
VL - 38
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 7
M1 - e00566-17
ER -