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AT1R autoantibody impedes fetal hepatic glycogen synthesis by inhibiting PI3K/AKT signaling pathway during late
Jingwei Bian1,2, Wang Wang1,3, Pengli Wang1
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 Xitoutiao, You An Men Street, Beijing, 100069, People's Republic of China.
Background:
Fetal hepatic glycogen is essential for intrauterine development and postnatal metabolic adaptation. This study aimed to explore the impact of intrauterine exposure to angiotensin II type 1 receptor autoantibodies (AT1-AA) on fetal hepatic glycogen homeostasis and underlying mechanisms.
Methods:
AT1-AA-positive pregnant rat models were established by intravenous administration of AT1-AA on gestational days 13 and 15, with angiotensin II- and L-NAME-treated groups serving as controls. Serum levels of AT1-AA in pregnant rats were quantified using ELISA. Fetal hepatic glycogen content was evaluated through PAS staining and an anthrone-sulfuric acid assay kit. On gestational day 18, fetal livers were harvested for RNA sequencing. Alterations in signaling molecules in hepatocytes were analyzed by Western blot.
Results:
Unlike the angiotensin II- and L-NAME-treated groups, which similarly induced placental ischemia and growth restriction, intrauterine exposure of AT1-AA uniquely reduced fetal hepatic glycogen content at gestational day 18. This reduction was attributed to impaired glycogen synthesis, as characterized by decreased GYS2 expression and glycogen synthase activity. Transcriptomic profiling revealed that suppression of the PI3K/AKT pathway was the predominant mechanism involved. Both in vivo and in vitro studies confirmed that AT1-AA-mediated PI3K/AKT inhibition occurs through AT1R activation. Either stimulation of the PI3K/AKT pathway or blockade of AT1R significantly restored glycogen synthesis.
Conclusions:
Our study identifies AT1-AA as a unique maternal factor that selectively impairs fetal hepatic glycogen storage via AT1R-mediated suppression of PI3K/AKT pathway.
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