title: Neurokinin 3 receptor and phosphocholine transferase: missing factors for pathogenesis of C-reactive protein in preeclampsia.
abstract: C-reactive protein (CRP), an innate immune mediator, is elevated in the circulation before symptoms in patients with preeclampsia, a severe hypertensive pregnancy disorder with high mortality and morbidity. However, the specific sources underlying increased CRP and the role of elevated CRP in preeclampsia are undefined. Here, we report that circulating CRP levels are significantly increased in a large cohort of normotensive pregnant individuals when compared with nulligravid women and is further increased in patients with preeclampsia. These findings led us to discover further that placental syncytiotrophoblasts are previously unrecognized cellular sources of CRP and underlie elevated CRP in normotensive pregnant women and the additional increase in patients with preeclampsia. Next, we demonstrated that injection of CRP induces preeclampsia features, including hypertension (157 mm Hg CRP treated versus 119 mm Hg control), proteinuria (35.0 mg/μg CRP treated versus 14.1 mg/μg control), kidney, and placental damage and increased levels of sFlt-1 in pregnant mice but not in nonpregnant mice. Our study implicates that phosphocholine transferase, a placental-specific enzyme post-translationally modifying neurokinin B, is essential for the pathogenic role of CRP in preeclampsia through activation of the neurokinin 3 receptor. Overall, our studies have provided significant new insight on the pathogenic role of CRP in preeclampsia and highlighted innovative therapeutic strategies.
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parchim
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iriyama
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Olaide A
authors.initials: OA
authors.lastname: Ashimi
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Athar H
authors.initials: AH
authors.lastname: Siddiqui
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Sean
authors.initials: S
authors.lastname: Blackwell
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Baha
authors.initials: B
authors.lastname: Sibai
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.).
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: From the Departments of Biochemistry and Molecular Biology (N.F.P., W.W. T.I., A.H.S., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (O.A.A., S.B., B.S.), Graduate School of Biomedical Science (N.F.P., R.E.K. Y.X.), University of Texas, Houston; Department of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan, China (W.W., Y.X.); Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan (T.I.); and School of Medical Sciences, University of Hyderabad, Gachibowli, Hyderabad, India (A.H.S.). yang.xia@uth.tmc.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D015415:Biomarkers; D002097:C-Reactive Protein / Q000032:analysis / Q000502:physiology* / Q000633:toxicity; D019916:Choline-Phosphate Cytidylyltransferase / Q000037:antagonists & inhibitors / Q000502:physiology*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D015287:Neurokinin B / Q000378:metabolism*; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000378:metabolism; D010920:Placenta / Q000473:pathology; D011225:Pre-Eclampsia / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000633:toxicity; D016037:Single-Blind Method; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
chemical_list: D015415:Biomarkers; D011804:Quinolines; D034741:RNA, Small Interfering; D018042:Receptors, Neurokinin-3; D011994:Recombinant Proteins; C109112:SB 222200; D010767:Phosphorylcholine; D015287:Neurokinin B; D002097:C-Reactive Protein; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C476147:CTP phosphocholine cytidylyltransferase, beta isoform, mouse; D019916:Choline-Phosphate Cytidylyltransferase; C545697:PCYT1B protein, human
keywords: C-reactive protein; inflammation; neurokinin B; phosphocholine transferase