Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies

Rolfo, Alessandro; Many, Ariel; Racano, Antonella; Tal, Reshef; Tagliaferro, Andrea; Ietta, Francesca; Wang, Jinxia; Post, Martin; Caniggia, Isabella

doi:10.1371/journal.pone.0013288

Cited by 100 publications

(100 citation statements)

References 71 publications

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“…We have previously reported that aberrant oxygen sensing mediated by PHDs is a defining feature of E-PE (26). Hence, we examined JMJD6 expression in human placentae from E-PE and L-PE.…”

Section: Jmjd6 Is Elevated In Severe E-pe Placentaementioning

confidence: 99%

Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta

2015

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Persistent low oxygen is implicated in the pathogenesis of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Emerging evidence implicates a novel family of Jumonji C catalytic domain proteins as mediators of hypoxic gene expression. Here, we investigated the regulatory relationship between Jumonji C domain containing protein 6 (JMJD6) and hypoxia-inducible factor (HIF)1A in the human placenta at physiological and pathological conditions. JMJD6 expression inversely correlated with changes in oxygen tension during early placental development, ie, high at 7-9 weeks when-partial pressure of O2 is low and declining afterwards when-partial pressure of O2 increases. Moreover, JMJD6 protein was significantly elevated in early-onset preeclamptic placentae, localizing to the syncytiotrophoblast layer and syncytial knots. Exposure of primary isolated trophoblast cells, human villous explants, and JEG3 choriocarcinoma cells to low oxygen (3%) and sodium nitroprusside (inducer of oxidative stress) also resulted in elevated JMJD6 levels, which was abrogated by HIF1A knockdown. In normoxia, knockdown of JMJD6 in JEG3 cells stabilized HIF1A with a concomitant decrease in von Hippel-Lindau (VHL) tumor suppressor protein, a negative regulator of HIF1A stability. In contrast, overexpression of JMJD6 enhanced VHL expression and destabilized HIF1A. JMJD6 regulation of VHL stability did not involve the ubiquitin-proteasome system but likely occurred through lysyl hydroxylation and small ubiquitin-like modifier 1-dependent small ubiquitin-like modifierylation. In summary, our data signify a novel role for JMJD6 as an oxygen sensor in the human placenta, and alterations in the JMJD6-VHL-HIF1A feedback loop may indirectly contribute to elevated HIF1A found in preeclampsia.

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“…We have previously reported that aberrant oxygen sensing mediated by PHDs is a defining feature of E-PE (26). Hence, we examined JMJD6 expression in human placentae from E-PE and L-PE.…”

Section: Jmjd6 Is Elevated In Severe E-pe Placentaementioning

confidence: 99%

Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta

2015

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“…It is now apparent from studies into pregnancy-induced preeclampsia that both the severity of the disease and the birth outcomes are dependent on whether maternal complications commence in early or late pregnancy [27,28]. A comparable situation may also occur with regard to potential adverse effects of maternal obesity as well as gestational diabetes (irrespective of maternal body weight before pregnancy).…”

Section: How Do Maternal Obesity and Diet Influence The Early Nutritimentioning

confidence: 99%

Early Life Nutritional Programming of Obesity: Mother-Child Cohort Studies

et al. 2013

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Background: The obesity epidemic has resulted in more overweight/obese women before and during pregnancy. Their offspring tend to have higher birth weights and more body fat, and carry an increased risk of obesity later in life. These effects may partly be related to the heightened risk of gestational diabetes, occurring in at least 16% of all pregnancies irrespective of current body weight. Methods: An ILSI Europe workshop reviewed the key contributors leading to adverse outcomes in pregnancy and childhood, including gestational weight gain and nutrition. New research opportunities from prospective mother-child cohort studies were explored. Results: Simple measures of gestational weight gain provide insufficient detail of the underlying physiological and metabolic adaptations occurring in pregnancy, and should be complemented by measures of body composition, metabolic and endocrine responses. Recordings of maternal dietary intake and nutrient status are often limited and potential correlations with gestational weight gain have been poorly studied. Many pregnancies in overweight/obese women are uncomplicated and result in offspring of normal weight, leaving the main determinants of later adverse outcomes to be clarified. Conclusions: The workshop provided insights of primary measurements for the characterization of sustainable nutritional intervention strategies in the mother, infant and child for preventing obesity in later life.

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“…Another 10 blood experimental biomarkers (AT-1AA [31], calcyclin, copeptin [34], galectin-1 [36], Gas6 [37], HIF-1aOH [38], IGFALS [41], mammalian HtrA3 [45], NT-proBNP [47], and PTX3 [49]), and four urine ones (C5b-9 [33], nephrin [46], iodine [42], and prolactin [52]) had limited clinical evaluation information, which impeded the evaluation of their performance for the diagnosis of PE. No clinical data were found for the remaining nine blood markers, which consisted of adipsin, α enolase, ADMA, Ba, 2,3-BPGM, Fetal DNA, marinobufagenin, plasma UA [51], and soluble CD117.…”

Section: Resultsmentioning

confidence: 99%

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings

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Goett

Lee

et al. 2016

Clinical Chemistry and Laboratory Medicine (CCLM)

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Abstract:In recent years, an increasing amount of literature is emerging on candidate urine and blood-based biomarkers associated with incidence and severity of preeclampsia (PE) in pregnant women. While enthusiasm on the usefulness of several of these markers in predicting PE is evolving, essentially all work so far has focused on the needs of high-resource settings and high-income countries, resulting primarily in multi-parameter laboratory assays based on proteomic and metabolomics analysis techniques. These highly complex methods, however, require laboratory capabilities that are rarely available or affordable in low-resource settings (LRS). The importance of quantifying maternal and perinatal risks and identifying which pregnancies can be safely prolonged is also much greater in LRS, where intensive care facilities that can rapidly respond to PE-related health threats for women and infants are limited. For these reasons, simple, low cost, sensitive, and specific point-of-care (POC) tests are needed that can be performed by antenatal health care providers in LRS and that can facilitate decisions about detection and management of PE. Our study aims to provide a comprehensive systematic review of current and emerging blood and urine biomarkers for PE, not only on the basis of their clinical performance, but also of their suitability to be used in LRS-compatible test formats, such as lateral flow and other variants of POC rapid assays.

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Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies

Cited by 100 publications

References 71 publications

Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta

Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta

Early Life Nutritional Programming of Obesity: Mother-Child Cohort Studies

Towards biomarker-based tests that can facilitate decisions about prevention and management of preeclampsia in low-resource settings

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