An essential role for angiotensin II type 1a receptor in pregnancy-associated hypertension with intrauterine growth retardation.
Little is known about an in vivo significance of angiotensin II Type-1 receptor (AT1) for pregnancy-associated diseases, including hypertension and intrauterine growth retardation (IUGR). We previously demonstrated that female mice carrying the human angiotensinogen gene (hAG+/+), when mated with human renin transgenic (hRN+/+) male mice, displayed hypertension in late pregnancy due to secretion of human renin from the fetal side into the maternal circulation. In the present study, to investigate a role for AT1 in pregnancy-associated hypertension, we generated a new strain of hAG+/+/mAT1a-/- mice by genetically deleting the AT1a gene from hAG+/+ mice. When mated with hRN+/+ male mice, excessive increases in human renin, angiotensin, and plasma renin activity were detected in the plasma of pregnant hAG+/+/mAT1a-/- mice as found in that of pregnant hAG+/+ mice. Surprisingly, however, blood pressure of hAG+/+/mAT1a-/- mice was not elevated in late pregnancy despite the presence of AT1b, a subtype of AT1. The maternal and fetal defects, such as cardiac and placental abnormalities, and IUGR observed in pregnant hypertensive hAG+/+ mice were not recognized in pregnant hAG+/+/mAT1a-/- mice. The limited term administration of AT1 antagonists to hypertensive hAG+/+ mice in late pregnancy dramatically improved hypertension and IUGR, showing the clinical importance of AT1a.
Saito
Tomoko
T
Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Ishida
Junji
J
Takimoto-Ohnishi
Eriko
E
Takamine
Shoko
S
Shimizu
Taku
T
Sugaya
Takeshi
T
Kato
Hideki
H
Matsuoka
Toshiki
T
Nangaku
Masaomi
M
Kon
Yasuhiro
Y
Sugiyama
Fumihiro
F
Yagami
Ken-ichi
K
Fukamizu
Akiyoshi
A
D047228:Angiotensin II Type 1 Receptor Blockers; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D003433:Crosses, Genetic; D005260:Female; D005317:Fetal Growth Retardation / Q000150:complications* / Q000503:physiopathology*; D017353:Gene Deletion; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010920:Placenta / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000097:blood / Q000235:genetics / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D012083:Renin