title: Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia.
abstract: BACKGROUND
  Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy associated with autoantibodies, termed AT1-AA, that activate the AT1 angiotensin receptor. Although the pathogenic nature of these autoantibodies has been extensively studied, little is known about the molecular cause of their generation.
  
  
  RESULTS
  Here we show that tissue transglutaminase (TG2), an enzyme that conducts posttranslational modification of target proteins, directly modified the 7-amino acid (7-aa) epitope peptide that localizes to the second extracellular loop of the AT1 receptor. These findings led us to further discover that plasma transglutaminase activity was induced and contributed to the production of AT1-AA and disease development in an experimental model of PE induced by injection of LIGHT, a tumor necrosis factor superfamily member. Key features of PE were regenerated by adoptive transfer of purified IgG from LIGHT-injected pregnant mice and blocked by the 7-amino acid epitope peptide. Translating our mouse research to humans, we found that plasma transglutaminase activity was significantly elevated in PE patients and was positively correlated with AT1-AA levels and PE features.
  
  
  CONCLUSIONS
  Overall, we provide compelling mouse and human evidence that elevated transglutaminase underlies AT1-AA production in PE and highlight novel pathogenic biomarkers and innovative therapeutic possibilities for the disease.
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.).
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.) Nephrology Department, Xiangya Hospital, Hunan, China (R.L., W.W.) Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, China (R.L.).
authors.forename: Renna
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, CA (S.E.E., P.S.D., Y.X.).
authors.forename: Serra E
authors.initials: SE
authors.lastname: Elliott
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.) Nephrology Department, Xiangya Hospital, Hunan, China (R.L., W.W.).
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.).
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Parchim
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.) Department of Obstetrics and Gynecology, University of Tokyo, Japan (T.I.).
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iriyama
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara, CA (S.E.E., P.S.D., Y.X.).
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Daugherty
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, TX (S.C.B., B.M.S.).
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston, TX (S.C.B., B.M.S.).
authors.forename: Baha M
authors.initials: BM
authors.lastname: Sibai
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.) The University of Texas Graduate School of Biomedical Sciences at Houston, TX (R.E.K., Y.X.).
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.affiliation: Departments of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, TX (C.L., R.L., W.W., N.F.P., T.I., R.E.K., Y.X.) The University of Texas Graduate School of Biomedical Sciences at Houston, TX (R.E.K., Y.X.) Department of Chemical Engineering, University of California, Santa Barbara, CA (S.E.E., P.S.D., Y.X.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D000939:Epitopes / Q000276:immunology; D005260:Female; D019204:GTP-Binding Proteins / Q000097:blood / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011225:Pre-Eclampsia / Q000209:etiology* / Q000503:physiopathology; D011247:Pregnancy; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D011945:Receptors, Angiotensin / Q000502:physiology*; D011503:Transglutaminases / Q000097:blood / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D000939:Epitopes; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: AT1‐AA; autoimmunity; preeclampsia; transglutaminase