title: Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model.
abstract: Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.
authors.affiliation: Departments of Pediatrics and Pathology, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Satyan S
authors.initials: SS
authors.lastname: Kalkunte
authors.affiliation: Department of Obstetrics, Institute of Human Genetics, University of Jena, Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubeck
authors.affiliation: Departments of Pediatrics and Pathology, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Wendy E
authors.initials: WE
authors.lastname: Norris
authors.affiliation: Departments of Pediatrics and Pathology, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Shi-Bin
authors.initials: SB
authors.lastname: Cheng
authors.affiliation: Departments of Pediatrics and Pathology, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kostadinov
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island.
authors.forename: Dang
authors.initials: D
authors.lastname: Vu Hoang
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island.
authors.forename: Aftab
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Department of Obstetrics, Institute of Human Genetics, University of Jena, Jena, Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: von Eggeling
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Shaikh
authors.affiliation: Departments of Pediatrics and Pathology, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: James
authors.initials: J
authors.lastname: Padbury
authors.affiliation: Division of Obstetrics and Gynecology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Goran
authors.initials: G
authors.lastname: Berg
authors.affiliation: Department of Medical Chemistry, Umea University, Umea, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Olofsson
authors.affiliation: Department of Obstetrics, Institute of Human Genetics, University of Jena, Jena, Germany.
authors.forename: Udo R
authors.initials: UR
authors.lastname: Markert
authors.affiliation: Departments of Pediatrics and Pathology, Women and Infants Hospital-Warren Alpert Medical School of Brown University, Providence, Rhode Island. Electronic address: ssharma@wihri.org.
authors.forename: Surendra
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000071063:Endoglin; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic; D011225:Pre-Eclampsia / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D040901:Proteomics; D012995:Solubility; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011228:Prealbumin; D016753:Interleukin-10; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
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