Transthyretin Is Dysregulated in Preeclampsia, and Its Native Form Prevents the Onset of Disease in a Preclinical Mouse Model

• Published in: The American journal of pathology Vol. 183; no. 5; pp. 1425 - 1436
• Main Authors: Kalkunte, Satyan S, Neubeck, Stefan, Norris, Wendy E, Cheng, Shi-Bin, Kostadinov, Stefan, Vu Hoang, Dang, Ahmed, Aftab, von Eggeling, Ferdinand, Shaikh, Zahir, Padbury, James, Berg, Goran, Olofsson, Anders, Markert, Udo R, Sharma, Surendra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2013; American Society for Investigative Pathology
• Subjects: Animals; Disease Models, Animal; Endoglin; Female; Humans; Immunoprecipitation; Interleukin-10 - deficiency; Interleukin-10 - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; MEDICIN; MEDICINE; Mice; Neovascularization, Physiologic; Pathology; Pre-Eclampsia - blood; Pre-Eclampsia - metabolism; Pre-Eclampsia - pathology; Prealbumin - chemistry; Prealbumin - metabolism; Pregnancy; Protein Binding; Protein Structure, Quaternary; Proteomics; Regular; Solubility; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Vascular Endothelial Growth Factor Receptor-1 - metabolism
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2013.07.022

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.