title: An essential role for angiotensin II type 1a receptor in pregnancy-associated hypertension with intrauterine growth retardation.
abstract: 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.
authors.affiliation: Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Saito
authors.forename: Junji
authors.initials: J
authors.lastname: Ishida
authors.forename: Eriko
authors.initials: E
authors.lastname: Takimoto-Ohnishi
authors.forename: Shoko
authors.initials: S
authors.lastname: Takamine
authors.forename: Taku
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Hideki
authors.initials: H
authors.lastname: Kato
authors.forename: Toshiki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kon
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sugiyama
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yagami
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
mesh_terms: 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
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; D012083:Renin