Peripheral RAGE (Receptor for Advanced Glycation Endproducts)-ligands in normal pregnancy and preeclampsia: novel markers of inflammatory response

Naruse, Katsuhiko; Sado, Toshiyuki; Noguchi, Taketoshi; Tsunemi, Taihei; Yoshida, Shozo; Akasaka, Juria; Koike, Nobuyuki; Oi, Hidekazu; Kobayashi, Hiroshi

doi:10.1016/j.jri.2011.12.003

Cited by 51 publications

(42 citation statements)

References 26 publications

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“…13) As expected from previously reported serum concentrations, 15) our current study strongly suggests that hypoxia and reoxygenation in the preeclamptic placenta contributes to systemic release of the danger signal HMGB1. Cellular debris (microparticles) from syncytiotrophoblasts is regarded as a possible mediator of the systemic inflammation that connects placentation failure in the first trimester to later onset of preeclampsia; HMGB1 and S100 family members are considered candidate functional surface antigen molecules on the microparticles.…”

Section: )supporting

confidence: 88%

“…There is no established evidence that HMGB1 contributes to the pathology of preeclampsia, although some publications, including our own, 15,16) suggest a relationship between HMGB1 and preeclampsia. 13) As expected from previously reported serum concentrations, 15) our current study strongly suggests that hypoxia and reoxygenation in the preeclamptic placenta contributes to systemic release of the danger signal HMGB1.…”

Section: )mentioning

confidence: 85%

“…13,14) We subsequently reported increased serum levels of two soluble RAGE ligands in preeclampsia patients, high-mobility group box 1 (HMGB1) and S100/calgranulin family member S100A12 (also known as extracellular newly identified RAGE-binding protein). 15) HMGB1 expression has also been reported in human term placenta. 16,17) In preeclamptic patients, HMGB1 expression tends to increase in the placenta 17) or decidua.…”

Section: Introductionmentioning

confidence: 84%

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Cytokines, proteases, and ligands of receptor for advanced glycation endproducts (RAGE) released by primary trophoblasts from human term placenta under hypoxic stimulation

Naruse

Tsunemi

Onogi

et al. 2013

Hypertens Res Pregnancy

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Aim:In the placenta, hypoxia followed by reoxygenation (ischemia and reperfusion) is regarded as a trigger for the pathological onset of preeclampsia. In this study, we isolated primary trophoblasts from human term placenta, exposed them to hypoxic stress, and measured subsequent levels of cytokines, proteases, protease inhibitors, and ligands of receptor for advanced glycation endproducts (RAGE) to identify the trigger molecule released from hypoxic placenta into maternal circulation. Methods: Ten placental samples were taken from healthy elective caesarean section patients. Trophoblasts were isolated using a Percoll-based method and cultured under 20% oxygen with or without 3 rounds of 0.1% hypoxic stimulation for 1 h. Results: Cell viability did not differ between normal and hypoxic cultures (MTT assay), but cell injury was attenuated in hypoxic culture (LDH assay). In cell culture supernatants, concentrations of MMP-2, TIMP-2, IL-6, and IL-10 decreased in hypoxia compared to normal culture, while the RAGE ligand HMGB1 increased significantly in hypoxic culture. There were no significant differences in concentrations of MMP-9, TIMP-1, IL-8, or S100A12. Conclusions: These results suggest that human term placenta under hypoxia and reperfusion releases the RAGE ligand HMGB1, a "danger signal", that can trigger systemic inflammation and lead to preeclampsia or placenta-based complications in pregnancy.

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Section: )supporting

confidence: 88%

Section: )mentioning

confidence: 85%

Section: Introductionmentioning

confidence: 84%

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Cytokines, proteases, and ligands of receptor for advanced glycation endproducts (RAGE) released by primary trophoblasts from human term placenta under hypoxic stimulation

Naruse

Tsunemi

Onogi

et al. 2013

Hypertens Res Pregnancy

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“…Trophoblast hypoxia, caused by defective placentation, is a key event in the pathogenesis of PE. Recently, reports have shown that serum HMGB1 levels are increased in severe PE, most notably in patients with early-onset PE (10). In addition, the expression of HMGB1 in the placenta from women with PE was higher than that of women with healthy pregnancies (51).…”

Section: Discussionmentioning

confidence: 96%

“…Postischemic inflammation is an essential step in the progression of endothelial cell injury in PE (8). A recent study showed that HMGB1 serum levels are increased in severe PE, most notably in patients experiencing early-onset PE (10). General edema and high urine protein are the main characteristics of early-onset PE.…”

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confidence: 99%

Hypoxic Trophoblast HMGB1 Induces Endothelial Cell Hyperpermeability via the TRL-4/Caveolin-1 Pathway

Jiang¹,

Cai

Zhu

et al. 2014

The Journal of Immunology

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High mobility group box 1 (HMGB1) plays an important role in the pathologic processes of endothelial permeability under oxidative stress. Trophoblast oxidative stress has been implicated in the pathophysiology of preeclampsia (PE). HMGB1 serum levels are increased in PE. However, the potential roles of HMGB1 in endothelial permeability in PE remain unclear. We assessed the effects of the hypoxic trophoblast on the permeability of the endothelial monolayer. Our results showed that the hypoxic trophoblast displayed higher HMGB1 mRNA, intracellular HMGB1 protein, and HMGB1 in conditioned medium than those of the normoxic trophoblast did. The hypoxic trophoblast conditioned medium increased the endothelial monolayer permeability and increased TLR 4 and caveolin-1 (CAV-1) protein expression in endothelial cells, which was inhibited by glycyrrhizic acid and HMGB1 small interfering RNA transfection to trophoblasts before hypoxia. The increased endothelial permeability induced by hypoxic trophoblast conditioned medium could be inhibited with TLR4 or CAV-1 gene silencing in endothelial cells. Immunoprecipitation showed that CAV-1 and TLR4 are colocalized in HUVECs and C57BL/6 mouse kidney. TLR4 small interfering RNA suppressed CAV-1 protein expression in endothelial cells upon stimulation of hypoxic trophoblast conditioned medium or HMGB1. We conclude that hypoxic trophoblasts play an important role in the mechanism of general edema (including protein urine) in PE via increasing endothelial monolayer permeability through the HMGB1/TLR4/CAV-1 pathway.

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Increased serum levels of high mobility group protein B1 and calprotectin in pre‐eclampsia

Huang

Wang

et al. 2018

Intl J Gynecology & Obste

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Peripheral RAGE (Receptor for Advanced Glycation Endproducts)-ligands in normal pregnancy and preeclampsia: novel markers of inflammatory response

Cited by 51 publications

References 26 publications

Cytokines, proteases, and ligands of receptor for advanced glycation endproducts (RAGE) released by primary trophoblasts from human term placenta under hypoxic stimulation

Cytokines, proteases, and ligands of receptor for advanced glycation endproducts (RAGE) released by primary trophoblasts from human term placenta under hypoxic stimulation

Hypoxic Trophoblast HMGB1 Induces Endothelial Cell Hyperpermeability via the TRL-4/Caveolin-1 Pathway

Increased serum levels of high mobility group protein B1 and calprotectin in pre‐eclampsia

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