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SHR Neuro Cancer Cardio Lipid Metab Microb

Tandl, V; Hoch, D; Bandres-Meriz, J; Nikodijevic, S; Desoye, G; Majali-Martinez, A.
Different regulation of IRE1 alpha and eIF2 alpha pathways by oxygen and insulin in ACH-3P trophoblast model
REPRODUCTION. 2021; 162(1): 1-10. Doi: 10.1530/REP-20-0668
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Leading authors Med Uni Graz

Desoye Gernot

Tandl Veronika

Co-authors Med Uni Graz

Bandrés Mériz Julia

Hoch Denise

Majali Martinez Alejandro

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Abstract:

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% O-2) increased IRE1 alpha phosphorylation (+52%; P < 0.05) and XBP1 splicing (1.8-fold change; P <= 0.001) after 24 h, while eIF2 alpha protein and CHOP expression were downregulated (-28%; P < 0.05 and -24%; P <= 0.001; respectively). eIF2oc 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 IRE1 alpha and eIF2 alpha UPR-pathways are differentially regulated by oxygen and insulin in early pregnancy.

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