Placental autophagy failure: A risk factor for preeclampsia

Nakashima, Akitoshi; Saito, Tomoko; Aoki, Aiko; Kawaguchi, Mihoko; Yasuda, Ippei; Tsuda, S.; Yoneda, Satoshi; Yamaki-Ushijima, Akemi; Cheng, Shi-Bin; Sharma, Surendra; Saito, Shigeru

doi:10.1111/jog.14489

Cited by 11 publications

(7 citation statements)

References 64 publications

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“…Regarding mTOR, our results were in line with those of other authors showing that hyperactivation of protein expression in the placenta may be suggestive of an adaptive response to limited nutrient availability or to situations such as hypoxia, which occurs in the placenta of pregnant women with PE, and fetal growth restriction ( 29 ).…”

Section: Discussionsupporting

confidence: 91%

Down-regulation of autophagy proteins is associated with higher mTOR expression in the placenta of pregnant women with preeclampsia

Weel

Ribeiro

Romao‐Veiga

et al. 2022

Braz J Med Biol Res

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Autophagy is a lysosomal degradation pathway that removes protein aggregates and damaged organelles maintaining cellular integrity. It seems to be essential for cell survival during stress, starvation, hypoxia, and consequently to the placenta implantation and development. Preeclampsia (PE) is a multisystemic disorder characterized by the onset of hypertension associated or not with proteinuria and other maternal complications. Considering that the placenta seems to play an important role in the pathogenesis of PE, the objective of the present study was to evaluate protein levels of light chain protein (LC3), beclin-1, and the mammalian target of rapamycin (mTOR) in the placenta of pregnant women with PE. Placental tissues collected from 20 women with PE and 20 normotensive (NT) pregnant women were evaluated for LC3, beclin-1, and mTOR expression by qPCR and immunohistochemistry. The mRNA for LC3 and beclin-1 were significantly lower, while mTOR gene expression was significantly higher in the placenta of pregnant women with PE than in the NT group. Placentas of PE women showed significantly decreased protein expression of LC3-II and beclin-1, whereas mTOR was significantly increased compared with the NT pregnant women. There was a negative correlation between protein expression of mTOR and LC3-II in the placental tissue of PE women. In conclusion, the results showed autophagy deficiency suggesting that failure in this degradation process may contribute to the pathogenesis of PE; however, new studies involving cross-talk between autophagy and inflammatory molecular mechanisms might help to better understand the autophagy process in this obstetric pathology.

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Section: Discussionsupporting

confidence: 91%

Down-regulation of autophagy proteins is associated with higher mTOR expression in the placenta of pregnant women with preeclampsia

Weel

Ribeiro

Romao‐Veiga

et al. 2022

Braz J Med Biol Res

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“…Given the seeming importance of lysosomal and autophagy biology in placental cell differentiation, we were surprised by this finding. 54,55 In our study, even double KO of TFEB and TFE3 did not perturb many lysosomal and autophagy genes or the ability to produce lysosomes during differentiation (Fig. 3).…”

Section: Discussionsupporting

confidence: 46%

“…[35][36][37] In patients with the placental disease preeclampsia, protein levels of TFEB along with lysosomal proteins LAMP1 and LAMP2 are reduced in placental tissue compared to agematched controls. 38,39 Indeed, perturbation of mTOR signaling has been shown to affect trophoblast syncytialization: in BeWo cells, treatment with the mTOR inhibitor Rapamycin increases cell fusion and hCG production, while concomitant treatment with the mTOR activator MHY1485 erases these effects. 40 In contrast, for cases of fetal growth restriction (FGR), researchers have found reduced mTOR phosphorylation and excess cell-cell fusion.…”

Section: Introductionmentioning

confidence: 99%

TFEB controls syncytiotrophoblast differentiation

Esbin,

Dahal,

Fan

et al. 2024

Preprint

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During human development, a subset of differentiating fetal cells form a temporary organ, the placenta, which invades the uterine wall to support nutrient, oxygen, and waste exchange between the mother and fetus until birth. Most of the human placenta is formed by a syncytial villous structure which arises via cell-cell fusion of underlying fetal trophoblast stem cells. Genetic and functional studies have characterized the membrane protein fusogens, Syncytin-1 and Syncytin-2, that are both necessary and sufficient for human trophoblast cell-cell fusion. However, identification and characterization of upstream transcriptional regulators regulating their expression has been limited. Here, using CRISPR knockout in anin vitrocellular model of syncytiotrophoblast development (BeWo cells), we find that the transcription factor TFEB, mainly known as a regulator of autophagy and lysosomal biogenesis, is required for cell-cell fusion of syncytiotrophoblasts. TFEB translocates to the nucleus, exhibits increased chromatin interactions, and directly binds the Syncytin-1 and Syncytin-2 promoters to control their expression during differentiation. While TFEB appears to play an important role in syncytiotrophoblast differentiation, ablation of TFEB largely does not affect lysosomal gene expression or lysosomal biogenesis in differentiating BeWo cells, suggesting that TFEB plays an alternative role in placental cells.

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“…Placental oxidative stress has been suggested to be central to the pathogenesis of preeclampsia 7 , 61 , 62 , whereas impaired trophoblast migration/invasion and spiral artery remodeling are also documented as hallmarks of PE 8 , 63 – 68 . While autophagy is regulated by membrane trafficking pathways in many species from yeast to mammals (reviewed by 75 , 76 ), the failure of placental autophagy has been reviewed as a risk factor of PE 77 . In contrast to known functional roles of NR1D2 and PER3 proteins outside their capacity to generate circadian rhythms, less is known about CRY1.…”

Section: Discussionmentioning

confidence: 99%

Co-alterations of circadian clock gene transcripts in human placenta in preeclampsia

Zhou

Winn

Nguyen

et al. 2022

Sci Rep

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Pre-eclampsia (PE) is a hypertensive condition that occurs during pregnancy and complicates up to 4% of pregnancies. PE exhibits several circadian-related characteristics, and the placenta possesses a functioning molecular clock. We examined the associations of 17 core circadian gene transcripts in placenta with PE vs. non-PE (a mixture of pregnant women with term, preterm, small-for-gestational-age, or chorioamnionitis) using two independent gene expression datasets: GSE75010-157 (80 PE vs. 77 non-PE) and GSE75010-173 (77 PE and 96 non-PE). We found a robust difference in circadian gene expression between PE and non-PE across the two datasets, where CRY1 mRNA increases and NR1D2 and PER3 transcripts decrease in PE placenta. Gene set variation analysis revealed an interplay between co-alterations of circadian clock genes and PE with altered hypoxia, cell migration/invasion, autophagy, and membrane trafficking pathways. Using human placental trophoblast HTR-8 cells, we show that CRY1/2 and NR1D1/2 regulate trophoblast migration. A subgroup study including only term samples demonstrated that CLOCK, NR1D2, and PER3 transcripts were simultaneously decreased in PE placenta, a finding supported by CLOCK protein downregulation in an independent cohort of human term PE placenta samples. These findings provide novel insights into the roles of the molecular clock in the pathogenesis of PE.

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Placental autophagy failure: A risk factor for preeclampsia

Cited by 11 publications

References 64 publications

Down-regulation of autophagy proteins is associated with higher mTOR expression in the placenta of pregnant women with preeclampsia

Down-regulation of autophagy proteins is associated with higher mTOR expression in the placenta of pregnant women with preeclampsia

TFEB controls syncytiotrophoblast differentiation

Co-alterations of circadian clock gene transcripts in human placenta in preeclampsia

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