Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia

BACKGROUND: Preeclampsia (PE) is a life‐threatening hypertensive disorder of pregnancy associated with autoantibodies, termed AT (1)‐AA, that activate the AT (1) angiotensin receptor. Although the pathogenic nature of these autoantibodies has been extensively studied, little is known about the molecular cause of their generation. METHODS AND 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 AT (1) receptor. These findings led us to further discover that plasma transglutaminase activity was induced and contributed to the production of AT (1)‐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 AT (1)‐AA levels and PE features. CONCLUSIONS: Overall, we provide compelling mouse and human evidence that elevated transglutaminase underlies AT (1)‐AA production in PE and highlight novel pathogenic biomarkers and innovative therapeutic possibilities for the disease.