title: Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia.
abstract: Accumulation of hypoxia inducible factor-1α (HIF-1α) is commonly an acute and beneficial response to hypoxia, whereas chronically elevated HIF-1α is associated with multiple disease conditions, including preeclampsia, a serious hypertensive disease of pregnancy. However, the molecular basis underlying the persistent elevation of placental HIF-1α in preeclampsia and its role in the pathogenesis of preeclampsia are poorly understood. Here we report that Hif-1α mRNA and HIF-1α protein were elevated in the placentas of pregnant mice infused with angiotensin II type I receptor agonistic autoantibody, a pathogenic factor in preeclampsia. Knockdown of placental Hif-1α mRNA by specific siRNA significantly attenuated hallmark features of preeclampsia induced by angiotensin II type I receptor agonistic autoantibody in pregnant mice, including hypertension, proteinuria, kidney damage, impaired placental vasculature, and elevated maternal circulating soluble fms-like tyrosine kinase-1 levels. Next, we discovered that Hif-1α mRNA levels and HIF-1α protein levels were induced in an independent preeclampsia model with infusion of the inflammatory cytokine tumor necrosis factor superfamily member 14 (LIGHT). SiRNA knockdown experiments also demonstrated that elevated HIF-1α contributed to LIGHT-induced preeclampsia features. Translational studies with human placentas showed that angiotensin II type I receptor agonistic autoantibody or LIGHT is capable of inducing HIF-1α in a hypoxia-independent manner. Moreover, increased HIF-1α was found to be responsible for angiotensin II type I receptor agonistic autoantibody or LIGHT-induced elevation of Flt-1 gene expression and production of soluble fms-like tyrosine kinase-1 in human villous explants. Overall, we demonstrated that hypoxia-independent stimulation of HIF-1α gene expression in the placenta is a common pathogenic mechanism promoting disease progression. Our findings reveal new insight to preeclampsia and highlight novel therapeutic possibilities for the disease.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iriyama
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parchim
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Baha M
authors.initials: BM
authors.lastname: Sibai
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.).
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (T.I., W.W., N.F.P., A.S., R.E.K., Y.X.) and Obstetrics, Gynecology, and Reproductive Sciences (S.C.B., B.M.S.), The University of Texas Medical School at Houston; Graduate School of Biomedical Sciences, Graduate Program in Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston (N.F.P., R.E.K., Y.X.); Department of Nephrology, Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China (W.W., Y.X.); and Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.). yang.xia@uth.tmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005311:Fetal Hypoxia / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D051379:Mice; D010920:Placenta / Q000378:metabolism* / Q000503:physiopathology; D011225:Pre-Eclampsia / Q000503:physiopathology / Q000628:therapy*; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000032:analysis; D011897:Random Allocation; D044139:Receptor, Angiotensin, Type 2 / Q000008:administration & dosage; D012680:Sensitivity and Specificity; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D001323:Autoantibodies; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044139:Receptor, Angiotensin, Type 2; C491959:Tnfsf13 protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13
keywords: hypoxia inducible factor-1; preeclampsia; tumor necrosis factor superfamily member 14
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