Endothelin-1 Induces Endoplasmic Reticulum Stress by Activating the PLC-IP3 Pathway Implications for Placental Pathophysiology in Preeclampsia
2012 (English)In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 6, 2309-2320 p.Article in journal (Refereed) Published
Recent evidence implicates placental endoplasmic reticulum (ER) stress in the pathophysiological characteristics of preeclampsia. Herein, we investigate whether endothelin (ET)-1, which induces Ca2+ release from the ER, can induce placental ER stress. Loss of ER Ca2+ homeostasis impairs post-translational modification of proteins, triggering ER stress-response pathways. IHC confirmed the presence of both ET-1 and its receptors in the syncytiotrophoblast. Protein levels and immunoreactivity of ET-1 and the endothelin B receptor (ETBR) were increased in preeclamptic samples compared with normotensive controls. JEG-3 and BeWo choriocarcinoma cells treated with ET-1 displayed an increase in ER stress markers. ET-1 induced phospho-activation of the ETBR. Treating cells with BQ788, an ETBR antagonist, or small-interfering RNA knockdown of the receptor inhibited induction of ER stress. ET-1 also stimulated p-phospholipase C (PLC)gamma 1 levels. By using inhibitors of PLC activation, U73122, and the inositol 1,4,5-triphosphate (IP3) receptor, xestospongin-C, we demonstrated that ET-1 induces ER stress via the PLC-IP3 pathway. Furthermore, ET-1 levels increased in the syncytiotrophoblast of explants from normal placentas after hypoxia-reoxygenation in vitro. Conditioned medium from hypoxia-reoxygenation explants also contained higher ET-1 levels, which induced ER stress in JEG-3 cells that was abolished by an ET-1 neutralizing antibody. Collectively, the data show that ET-1 induced ER stress in trophoblasts via the ETBR and initiation of signaling through the PLC-IP3 pathway, with the potential for autocrine stimulation.
Place, publisher, year, edition, pages
2012. Vol. 180, no 6, 2309-2320 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-178683DOI: 10.1016/j.ajpath.2012.03.005ISI: 000305101300016OAI: oai:DiVA.org:uu-178683DiVA: diva2:542636