PMID- 35216082 OWN - NLM STAT- MEDLINE DCOM- 20220314 LR - 20220314 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 23 IP - 4 DP - 2022 Feb 10 TI - Divergent Regulation of Decidual Oxidative-Stress Response by NRF2 and KEAP1 in Preeclampsia with and without Fetal Growth Restriction. LID - 10.3390/ijms23041966 [doi] LID - 1966 AB - Utero-placental development in pregnancy depends on direct maternal-fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal-fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR. FAU - Mundal, Siv Boon AU - Mundal SB AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. AD - Women's Health and Perinatology Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, 9037 Tromso, Norway. FAU - Rakner, Johanne Johnsen AU - Rakner JJ AUID- ORCID: 0000-0002-2140-8211 AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. FAU - Silva, Gabriela Brettas AU - Silva GB AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. AD - Department of Gynecology and Obstetrics, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway. FAU - Gierman, Lobke Marijn AU - Gierman LM AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. AD - Department of Gynecology and Obstetrics, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway. FAU - Austdal, Marie AU - Austdal M AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. AD - Department of Gynecology and Obstetrics, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway. AD - Department of Research, Stavanger University Hospital, 4068 Stavanger, Norway. FAU - Basnet, Purusotam AU - Basnet P AUID- ORCID: 0000-0001-8612-9558 AD - Women's Health and Perinatology Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, 9037 Tromso, Norway. AD - Department of Obstetrics and Gynecology, University Hospital of Northern Norway, 9037 Tromso, Norway. FAU - Elschot, Mattijs AU - Elschot M AD - Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. AD - Department of Radiology and Nuclear Medicine, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway. FAU - Bakke, Siril Skaret AU - Bakke SS AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. FAU - Ostrop, Jenny AU - Ostrop J AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. FAU - Thomsen, Liv Cecilie Vestrheim AU - Thomsen LCV AUID- ORCID: 0000-0002-6787-8518 AD - Department of Gynecology and Obstetrics, Haukeland University Hospital, 5058 Bergen, Norway. AD - Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway. FAU - Moses, Eric Keith AU - Moses EK AD - Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia. FAU - Acharya, Ganesh AU - Acharya G AUID- ORCID: 0000-0002-1997-3107 AD - Women's Health and Perinatology Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, 9037 Tromso, Norway. AD - Department of Clinical Science, Division of Obstetrics and Gynecology, Intervention and Technology, Karolinska Institutet, 141 86 Stockholm, Sweden. FAU - Bjorge, Line AU - Bjorge L AUID- ORCID: 0000-0002-0240-2770 AD - Department of Gynecology and Obstetrics, Haukeland University Hospital, 5058 Bergen, Norway. AD - Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway. FAU - Iversen, Ann-Charlotte AU - Iversen AC AUID- ORCID: 0000-0001-7726-7684 AD - Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway. AD - Department of Gynecology and Obstetrics, St. Olavs Hospital, Trondheim University Hospital, 7030 Trondheim, Norway. LA - eng GR - 223255/The Research Council of Norway/ GR - 223250/The Research Council of Norway/ GR - N/A/Central Norway Regional Health Authority/ PT - Journal Article DEP - 20220210 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Antioxidants) RN - 0 (KEAP1 protein, human) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NFE2L2 protein, human) RN - Uterine Anomalies SB - IM MH - Adult MH - Antioxidants/metabolism MH - Decidua/*metabolism MH - Female MH - Fetal Growth Retardation/*metabolism MH - Fetus/metabolism MH - Humans MH - Kelch-Like ECH-Associated Protein 1/*metabolism MH - NF-E2-Related Factor 2/*metabolism MH - Oxidation-Reduction MH - Oxidative Stress/*physiology MH - Placenta/metabolism MH - Placentation/physiology MH - Pre-Eclampsia/*metabolism MH - Pregnancy MH - Trophoblasts/metabolism MH - Urogenital Abnormalities/metabolism MH - Uterus/abnormalities/metabolism PMC - PMC8875334 OTO - NOTNLM OT - KEAP1 OT - NRF2 OT - antioxidant capacity OT - decidua OT - fetal growth restriction OT - oxidative stress OT - preeclampsia OT - trophoblast COIS- The authors declare no conflict of interest. EDAT- 2022/02/27 06:00 MHDA- 2022/03/15 06:00 PMCR- 2022/02/10 CRDT- 2022/02/26 01:07 PHST- 2021/12/02 00:00 [received] PHST- 2022/02/04 00:00 [revised] PHST- 2022/02/07 00:00 [accepted] PHST- 2022/02/26 01:07 [entrez] PHST- 2022/02/27 06:00 [pubmed] PHST- 2022/03/15 06:00 [medline] PHST- 2022/02/10 00:00 [pmc-release] AID - ijms23041966 [pii] AID - ijms-23-01966 [pii] AID - 10.3390/ijms23041966 [doi] PST - epublish SO - Int J Mol Sci. 2022 Feb 10;23(4):1966. doi: 10.3390/ijms23041966.