Different regulation of IRE1α and eIF2α pathways by oxygen and insulin in ACH-3P trophoblast model

in Reproduction
Authors:
Veronika Tandl Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

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Denise Hoch Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

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Julia Bandres-Meriz Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

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Sanela Nikodijevic Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

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Gernot Desoye Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

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Alejandro Majali-Martinez Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria

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https://orcid.org/0000-0002-9009-5810

Correspondence should be addressed to G Desoye; Email: gernot.desoye@medunigraz.at
DOI:
https://doi.org/10.1530/REP-20-0668
Volume/Issue:
Volume 162: Issue 1
Page Range:
1–10
Article Type:
Research Article
Online Publication Date:
27 May 2021
Copyright:
© Society for Reproduction and Fertility 2021
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Endoplasmic reticulum (ER)-stress activates the unfolded protein response (UPR), which plays a (patho)physiological role in the placenta. Oxygen and hyperinsulinemia are major regulators of placental development. Thus, we hypothesized that oxygen, insulin and their interplay modulate ER-stress in early pregnancy. Using the human first-trimester trophoblast cell line ACH-3P, we quantified mRNA and protein of several members of UPR by RT-qPCR and Western blotting, respectively. ER-stress induction using tunicamycin and brefeldin A resulted in increased CHOP (4.6-fold change; P ≤ 0.001), XBP1 expression (1.7- and 1.3-fold change, respectively; P ≤ 0.001 and P < 0.05) and XBP1 splicing (7.9- and 12.8-fold change, respectively; P ≤ 0.001). We subsequently analyzed the effect of oxygen (6.5%, 2.5%), insulin (0.1–10 nM) and their interaction using ANCOVA adjusted for cell passage as co-variate. Although GRP78 protein remained unaffected, low oxygen (2.5% O2) increased IRE1α phosphorylation (+52%; P < 0.05) and XBP1 splicing (1.8-fold change; P ≤ 0.001) after 24 h, while eIF2α protein and CHOP expression were downregulated (−28%; P < 0.05 and −24%; P ≤ 0.001; respectively). eIF2α phosphorylation was also reduced after 48 h by low oxygen (−61%; P < 0.05) but increased in the presence of insulin (+46%; P ≤ 0.01). These changes were not PERK-mediated, since PERK phosphorylation and total protein were not altered. Overall, our results suggest that IRE1α and eIF2α UPR-pathways are differentially regulated by oxygen and insulin in early pregnancy.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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