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논문분류	춘계학술대회 초록집
제목	Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia
저자	Renna Luo* 1, 2, 3, Chen Liu3, Serra E Elliott4, Hongli Lin1, Lijian Tao2, Rodney E Kellems3, Yang Xia3
출판정보	2016; 2016(1):
키워드	AT1-AA, autoimmunity, preeclampsia, transglutaminase
초록	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. Methods: Pregnant C57Bl/6J mice (Harlan) were anesthetized with isofluorane, and 0.15 mL sterile PBS dissolved with or without recombinant mouse LIGHT (2 ng, R&D Systems) was introduced by retro-orbital sinus injection on gestation day (GD) 13.5 and 14.5. Some mice were also injected with 2.25 mg cystamine dihydrochloride (Sigma-Aldrich, MO) dissolved in the 0.15 mL sterile PBS to inhibit TGase activity. Since the retroorbital injections of cystamine dihydrochloride were only performed on GD 13.5 and 14.5 together with LIGHT molecules,to ensure a constant and effective cystamine treatment afterwards, these pregnant mice were also administered drinking water containing 0.9 g/L cystamine dihydrochloride throughout the rest of their pregnancy. 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 such as kidney damage 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. Conclusion: 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.
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