New Insights Into the Role of Placental Aquaporins and the Pathogenesis of Preeclampsia

Szpilbarg, Natalia; Martínez, Nora; Paola, Mauricio Di; Reppetti, Julieta; Medina, Yollyseth; Seyahian, Abril; Parodi, Mauricio Castro; Damiano, Alicia E.

doi:10.3389/fphys.2018.01507

Cited by 10 publications

(7 citation statements)

References 68 publications

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“…Spzilbarg et al suggested that the absence of AQP9 functionality may impair the lactate transfer, promote more ROS accumulation, and increase the hST apoptosis, triggering apoptotic syncytial aggregate release into maternal circulation producing systemic endothelial dysfunction in preeclampsia. 17 Our study showed that the mean serum concentration of AQP9 was greater in women with early-onset preeclampsia (722.22 AE 211.80 pg/ mL) than in the control group (499.97 AE 68.89 pg/mL, p < 0.001). We think that this result conclusively demonstrated the inflammation in the pathological process of early-onset preeclampsia.…”

Section: Discussionmentioning

confidence: 44%

“…As preeclampsia is a complex disease resulting from many concurrent mechanisms, AQP9 was considered to contribute as part of pathogenesis that gives rise to the diverse clinical signs of this disease. 17 To the best of our knowledge, no study to date has assessed circulating levels of AQP9 in preeclamptic patients. This study aimed to evaluate maternal serum AQP9 concentrations of pregnant women complicated with early-onset preeclampsia and compare them with the uncomplicated control group with normal blood pressure.…”

Section: Introductionmentioning

confidence: 99%

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Increased maternal serum aquaporin‐9 expression in pregnancies complicated with early‐onset preeclampsia

Ölmez

Oğlak

Özköse

2021

J of Obstet and Gynaecol

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Objectives We aimed to evaluate maternal serum aquaporin‐9 (AQP9) concentrations in patients with early‐onset preeclampsia and compare them with the uncomplicated control group with normal blood pressure. Methods This was a prospective case–control study including pregnant women who were diagnosed with early‐onset preeclampsia between 200/7–340/7 weeks of gestation. Demographic and clinical characteristics, complete blood count and biochemical parameters, and serum AQP9 concentrations were documented. A receiver operating characteristic (ROC) curve was constructed to illustrate the sensitivity and specificity performance characteristics of AQP9 and a cut‐off value was estimated by using the Youden index. Results The mean serum concentrations of maternal AQP9 were significantly increased in the early‐onset preeclampsia group (722.22 ± 211.80 pg/mL) than the control group (499.97 ± 68.89 pg/mL, p < 0.001). When we analyze the area under the ROC curve (AUC), the serum AQP9 value can be considered a statistically significant parameter for diagnosing preeclampsia. According to the Youden index, a 587.70 ng/mL cut‐off value of serum AQP9 level can be used to diagnose early‐onset preeclampsia with 80.0% sensitivity and 89.7% specificity. Conclusion Maternal serum AQP9 concentrations were significantly increased in early‐onset preeclampsia patients than healthy normotensive pregnant patients. We suggest that AQP9 might be a crucial biomarker of the inflammatory process in early‐onset preeclampsia.

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Section: Discussionmentioning

confidence: 44%

Section: Introductionmentioning

confidence: 99%

Increased maternal serum aquaporin‐9 expression in pregnancies complicated with early‐onset preeclampsia

Ölmez

Oğlak

Özköse

2021

J of Obstet and Gynaecol

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“…Regarding AQP3, we recently reported that this protein was considerably decreased in preeclamptic placentas (Szpilbarg & Damiano, 2017). Although these changes in AQP3 and Cav-1 were found at the end of the preeclamptic gestation and in VT cells, we propose that the abnormal expression of both proteins could take place during the first stages of differentiation of the trophoblast stem cells and persist after their subsequent differentiation in extravillous and VT affecting both lineages (Szpilbarg et al, 2018).…”

Section: Aqp3 Colocalizes With Cav-1mentioning

confidence: 82%

Intact caveolae are required for proper extravillous trophoblast migration and differentiation

Reppetti

Reca

Seyahian

et al. 2019

Journal Cellular Physiology

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Caveolae constitute membrane domains critical for the organization and synchronization of different signaling molecules related to numerous cell processes such as cell migration, invasion, and differentiation. Caveolin-1 (Cav-1) is the main integral membrane protein of these domains. Recently, it was found that a normal expression of aquaporin-3 (AQP3) is required for extravillous trophoblast (EVT) cell migration.Our aim was to investigate the role of caveolae in the migration, invasion, and endovascular differentiation of human EVT cells during placentation and its interaction with AQP3. EVT cells (Swan 71 cell line) were cultured in complete Dulbecco's modified Eagle's medium-nutrient mixture F12 and treated with 5 mM methyl-β-cyclodextrin (MβCD) to disrupt caveolae. We found that after MβCD treatment, Cav-1 protein was undetectable. In this condition, the ability of the cells to migrate was significantly decreased compared with the control cells, while no differences were observed in the number of invading cells and the metalloproteinases activity between control and MβCD-treated cells. Surprisingly, the disruption of caveolae significantly enhanced EVT endovascular differentiation. On the contrary, the silencing of AQP3, negatively affected tube-like formation. The theoretical analysis of the primary sequence of AQP3 protein revealed a putative Cav-1-binding site. In addition, immunoprecipitation and double immunofluorescence assays showed that AQP3 colocalized with Cav-1. These results showed that during placentation an intact caveola in EVT cells may be necessary for AQP3 and Cav-1 interaction and any perturbations might result in serious pregnancy disorders.

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“…Thus, any alteration in NADH production may give rise to ROS accumulation triggering cell damage and finally leading to cell death (Miki et al, 2013). In this regard, there is considerable evidence that ROS promotes the apoptotic death of villous trophoblasts (Szpilbarg et al, 2016(Szpilbarg et al, , 2018Marín et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…However, functional experiments showed that water and monocarboxylate transport mediated by AQP9 were dramatically reduced ( Damiano et al, 2006 ). Notwithstanding this, there is no evidence of alterations in the transcellular water transport between the mother and the fetus, suggesting that the main role of AQP9 in the human placenta is not related to water transport ( Szpilbarg et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Lactic Acid Transport Mediated by Aquaporin-9: Implications on the Pathophysiology of Preeclampsia

et al. 2021

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Aquaporin-9 (AQP9) expression is significantly increased in preeclamptic placentas. Since feto-maternal water transfer is not altered in preeclampsia, the main role of AQP9 in human placenta is unclear. Given that AQP9 is also a metabolite channel, we aimed to evaluate the participation of AQP9 in lactate transfer across the human placenta. Explants from normal term placentas were cultured in low glucose medium with or without L-lactic acid and in the presence and absence of AQP9 blockers (0.3 mM HgCl2 or 0.5 mM Phloretin). Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release. Apoptotic indexes were analyzed by Bax/Bcl-2 ratio and Terminal Deoxynucleotidyltransferase-Mediated dUTP Nick-End Labeling assay. Heavy/large and light/small mitochondrial subpopulations were obtained by differential centrifugation, and AQP9 expression was detected by Western blot. We found that apoptosis was induced when placental explants were cultured in low glucose medium while the addition of L-lactic acid prevented cell death. In this condition, AQP9 blocking increased the apoptotic indexes. We also confirmed the presence of two mitochondrial subpopulations which exhibit different morphologic and metabolic states. Western blot revealed AQP9 expression only in the heavy/large mitochondrial subpopulation. This is the first report that shows that AQP9 is expressed in the heavy/large mitochondrial subpopulation of trophoblasts. Thus, AQP9 may mediate not only the lactic acid entrance into the cytosol but also into the mitochondria. Consequently, its lack of functionality in preeclamptic placentas may impair lactic acid utilization by the placenta, adversely affecting the survival of the trophoblast cells and enhancing the systemic endothelial dysfunction.

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New Insights Into the Role of Placental Aquaporins and the Pathogenesis of Preeclampsia

Cited by 10 publications

References 68 publications

Increased maternal serum aquaporin‐9 expression in pregnancies complicated with early‐onset preeclampsia

Increased maternal serum aquaporin‐9 expression in pregnancies complicated with early‐onset preeclampsia

Intact caveolae are required for proper extravillous trophoblast migration and differentiation

Lactic Acid Transport Mediated by Aquaporin-9: Implications on the Pathophysiology of Preeclampsia

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