A Role for RAGE in DNA Double Strand Breaks (DSBs) Detected in Pathological Placentas and Trophoblast Cells

Tsai, Kary Y F; Tullis, Benton; Breithaupt, Katrina L; Fowers, Rylan; Jones, Nelson F.; Grajeda, Samuel; Reynolds, Paul; Arroyo, Juan A.

doi:10.3390/cells10040857

Cited by 10 publications

(12 citation statements)

References 34 publications

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“…As a result, it is difficult to know what specifically is driving the alterations in protein levels that we have seen with FAN1 in the IUGR placenta and how this also does not comport directly with the patterns we would typically expect to see in the regulation of gene expression by DNA methylation. Previous studies have shown increased placental DNA damage including increases in dsDNA damage in the PE placenta [ 41 , 42 ]. The fact that FAN1 expression is decreased suggests that perhaps this could be a factor involved in the increased placental DNA damage during this disease.…”

Section: Discussionmentioning

confidence: 99%

“…CRAB1 was a gene hypomethylated only in the IUGR placenta. As previously mentioned, this gene produces the cellular retinoic acid-binding protein that is responsible for the delivery of Retinoic Acid (RA) to its receptors [ 42 ]. In our studies, hypomethylation of this gene led to decreased expression of the CRAB1 protein.…”

Section: Discussionmentioning

confidence: 99%

“…We observed decreases in the H4 protein in the PE placenta tissues. This is of interest as we have previously shown that PE placentas are associated with increased DNA damage [ 42 ]. Although there are no previous reports establishing a direct connection between H4 and PE, we can speculate that as observed with FAN1, decreased H4 could be associated with the increased DNA damage observed in PE placentas.…”

Section: Discussionmentioning

confidence: 99%

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Altered Epigenetic Profiles in the Placenta of Preeclamptic and Intrauterine Growth Restriction Patients

Norton

Clarke

Holmstrom

et al. 2023

Cells

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Intrauterine growth restriction (IUGR) and preeclampsia (PE) are placental pathologies known to complicate pregnancy and cause neonatal disorders. To date, there is a limited number of studies on the genetic similarity of these conditions. DNA methylation is a heritable epigenetic process that can regulate placental development. Our objective was to identify methylation patterns in placental DNA from normal, PE and IUGR-affected pregnancies. DNA was extracted, and bisulfite was converted, prior to being hybridized for the methylation array. Methylation data were SWAN normalized and differently methylated regions were identified using applications within the USEQ program. UCSC’s Genome browser and Stanford’s GREAT analysis were used to identify gene promoters. The commonality among affected genes was confirmed by Western blot. We observed nine significantly hypomethylated regions, two being significantly hypomethylated for both PE and IGUR. Western blot confirmed differential protein expression of commonly regulated genes. We conclude that despite the uniqueness of methylation profiles for PE and IUGR, the similarity of some methylation alterations in pathologies could explain the clinical similarities observed with these obstetric complications. These results also provide insight into the genetic similarity between PE and IUGR and suggest possible gene candidates plausibly involved in the onset of both conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Altered Epigenetic Profiles in the Placenta of Preeclamptic and Intrauterine Growth Restriction Patients

Norton

Clarke

Holmstrom

et al. 2023

Cells

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“…This genotype is characterized by lower sRAGE levels and higher risk factors for CVD, which has implicated it in diabetes and autoimmune diseases, such as Kawasaki disease [ 25 ]. Thus, abnormal upregulation and sRAGE activation are indicative of disease development and inflammatory and immune responses in the body [ 28 , 103 , 152 , 153 ]. Generally, increased levels of membrane-bound RAGE are associated with disease pathogenesis/injury because the ligands bound to fl-RAGE are able to transduce that signal intracellularly and stimulate the nuclear translocation of NF-κB, thus producing inflammation.…”

Section: Rage As a Biomarker Or Putative Therapeutic Targetmentioning

confidence: 99%

RAGE against the Machine: Can Increasing Our Understanding of RAGE Help Us to Battle SARS-CoV-2 Infection in Pregnancy?

Kurashima

Kendal-Wright

2022

IJMS

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The receptor of advanced glycation end products (RAGE) is a receptor that is thought to be a key driver of inflammation in pregnancy, SARS-CoV-2, and also in the comorbidities that are known to aggravate these afflictions. In addition to this, vulnerable populations are particularly susceptible to the negative health outcomes when these afflictions are experienced in concert. RAGE binds a number of ligands produced by tissue damage and cellular stress, and its activation triggers the proinflammatory transcription factor Nuclear Factor Kappa B (NF-κB), with the subsequent generation of key proinflammatory cytokines. While this is important for fetal membrane weakening, RAGE is also activated at the end of pregnancy in the uterus, placenta, and cervix. The comorbidities of hypertension, cardiovascular disease, diabetes, and obesity are known to lead to poor pregnancy outcomes, and particularly in populations such as Native Hawaiians and Pacific Islanders. They have also been linked to RAGE activation when individuals are infected with SARS-CoV-2. Therefore, we propose that increasing our understanding of this receptor system will help us to understand how these various afflictions converge, how forms of RAGE could be used as a biomarker, and if its manipulation could be used to develop future therapeutic targets to help those at risk.

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“…Abnormal placentation characterized by morphological and histological alterations in the placenta could result in diverse pregnancy complications such as GDM, preeclampsia, miscarriage, intrauterine growth restriction, and stillbirth. Dysregulation of steroids hormones synthesis is one of the important signs of placental dysfunction in various pregnancy-associated complications [9, 12, 13]. In this regard, Shin et al [14, 15] reported the dysregulation of steroidogenesis-related enzymes as well as steroid production in different models of the preeclamptic placenta.…”

Section: Introductionmentioning

confidence: 99%

Regulation of uterus and placenta remodeling under high estradiol levels in gestational diabetes mellitus models

Kang

Kim

Mohamed

et al. 2023

Biology of Reproduction

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The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of E2 in gestational diabetes mellitus (GDM). To achieve this, we established in vitro and in vivo models for GDM placentas by culturing BeWo cells under hyperglycemic concentration, and treating pregnant rats with streptozotocin (STZ). We evaluated the expression of angiogenesis-related proteins. The expression of the anti-angiogenic factor, excess placental soluble fms-like tyrosine kinase 1 (sFLT1) was increased in our in vitro GDM model compared to the control. Moreover, the expressions of placental sFLT1 and the von willebrand factor (VWF) were also significantly elevated in the placenta of STZ-treated rats. These data indicate the disruption of angiogenesis in the GDM placentas. The expression levels of connexin 43 (Cx43), a component of the gap junction and collagen type I alpha 2 chain (Col1a2), a component of the extracellular matrix, were decreased in the GDM uterus. These results suggest that uterus decidualization and placental angiogenesis are inhibited in GDM rats. Our results also showed upregulation of the expression of genes regulating E2 synthesis as well as estrogen receptors (ER) in vivo models. Accordingly, the concentration of E2 measured in the culture medium under hyperglycemic conditions, as well as in the serum and placenta of the STZ-treated rats, was significantly elevated compared to the control groups. These results suggest that the dysregulated remodeling of the placenta and uterus may result in the elevation of E2 and its signaling pathway in the GDM animal model to maintain pregnancy.

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A Role for RAGE in DNA Double Strand Breaks (DSBs) Detected in Pathological Placentas and Trophoblast Cells

Cited by 10 publications

References 34 publications

Altered Epigenetic Profiles in the Placenta of Preeclamptic and Intrauterine Growth Restriction Patients

Altered Epigenetic Profiles in the Placenta of Preeclamptic and Intrauterine Growth Restriction Patients

RAGE against the Machine: Can Increasing Our Understanding of RAGE Help Us to Battle SARS-CoV-2 Infection in Pregnancy?

Regulation of uterus and placenta remodeling under high estradiol levels in gestational diabetes mellitus models

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