title: NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.
abstract: Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Koumei
authors.initials: K
authors.lastname: Shirasuna
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Tadayoshi
authors.initials: T
authors.lastname: Karasawa
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Fumitake
authors.initials: F
authors.lastname: Usui
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Komada
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kawashima
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Ohkuchi
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Shun'ichiro
authors.initials: S
authors.lastname: Taniguchi
authors.affiliation: Division of Inflammation Research (K.S., T.Ka., F.U., M.K., T.Ko., H.K., A.K., M.T.), Center for Molecular Medicine, Department of Obstetrics and Gynecology (A.O.), Jichi Medical University, Tochigi 329-0498, Japan; Department of Animal Science (K.S.), Tokyo University of Agriculture, Kanagawa 243-0034, Japan; and Department of Molecular Oncology (S.T.), Shinshu University Graduate School of Medicine, Nagano 390-8621, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takahashi
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D046110:Hypertension, Pregnancy-Induced / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000804:Angiotensin II