PDIA3 regulates trophoblast apoptosis and proliferation in preeclampsia via the MDM2/p53 pathway

Abstract

Protein disulfide isomerase 3 (PDIA3) is a chaperone protein that modulates the folding of newly synthesized glycoproteins, has isomerase and redox activity, and has been implicated in the pathogenesis of many diseases. However, the role of PDIA3 in pregnancy-associated diseases remains largely unknown. Our present study reveals a key role for PDIA3 in the biology of placental trophoblasts from women with preeclampsia (PE). Immunohistochemistry and Western blot analysis revealed that PDIA3 expression was decreased in villous trophoblasts from women with PE compared to normotensive pregnancies. Further, using a Cell Counting Kit-8 assay, flow cytometry, and 5-ethynyl-2’-deoxyuridine (EdU) staining, we found that siRNA-mediated PDIA3 knockdown significantly promoted apoptosis and inhibited proliferation in the HTR8/SVneo cell line, while overexpression of PDIA3 reversed these effects. Furthermore, RNA sequencing and Western blot analysis demonstrated that knockdown of PDIA3 inhibited MDM2 protein expression in HTR8 cells, concurrent with marked elevation of p53 and p21 expression. Conversely, overexpression of PDIA3 had the opposite effects. Immunohistochemistry and Western blot further revealed that MDM2 protein expression was downregulated and p21 was increased in trophoblasts of women with PE compared to women with normotensive pregnancies. Our findings indicate that PDIA3 expression is decreased in the trophoblasts of women with PE, and decreased PDIA3 induces trophoblast apoptosis and represses trophoblast proliferation through regulating the MDM2/p53/p21 pathway.

Overexpression of ERAP2N in Human Trophoblast Cells Promotes Cell Death

“…Even though it was not in the top 50 DEGs and was not part of the top 12 genes we have focused on, it must be noted that PDIA3 is down-regulated in ERAP2N-expressing TCs. It was reported that PDIA3 expression was decreased in the TCs from women with PE, and decreased PDIA3 expression induced trophoblast apoptosis and repressed trophoblast proliferation by regulating the MDM2/p53/p21 pathway [38].…”

First-Trimester Serum Cytokine Profile in Pregnancies Conceived After Assisted Reproductive Technology (ART) With Subsequent Pregnancy-Induced Hypertension

“…The establishment and maintenance of pregnancy poses great challenges to the maternal immune system. Uncoordinated maternal immunization, especially in the first trimester of pregnancy, will be a potential cause of a series of pregnancy complications (47,48). Currently, immunotherapy has been applied to the treatment of a variety of reproductive diseases, such as recurrent spontaneous abortion (RSA) and recurrent implantation failure (RIF) (49), while the immunotherapy against PIH still needs a long way to go.…”

CLDN1 regulates trophoblast apoptosis and proliferation in preeclampsia

“…Moreover, Kalkat et al reported that the balance of BCL2 family proteins was altered towards cell death in preeclampsia ( Kalkat et al 2013 ). Recent studies have focused on trophoblast apoptosis caused by molecular dysfunction that leads to the disease ( Guo et al 2017 , Wang & Yan 2018 , Mo et al 2020 ). CLDN1 has been shown to be involved in apoptosis via alterations in the expression levels of Bcl-2 and Bax ( Singh et al 2012 , Zheng et al 2019 ), which was not detected in our study (Supplementary Fig.…”