CONICET | Buscador de Institutos y Recursos Humanos

Research Question: Recently, we reported that the blocking ofplacental aquaporins (AQPs) abrogates the apoptotic response of thetrophoblast. Because trophoblast apoptosis is exacerbated inpreeclampsia, we hypothesized that changes in AQPs in these placentas maytrigger the programmed cell death. Here, we investigated AQP4 expressionin preeclamptic placentas and its regulation by oxygen tension.Design: AQP4 expression was studied in normal placentas and placentasfrom preeclamptic pregnancies by RT-PCR, western blot,immunofluorescence, and immunohistochemistry. Explants from normalplacentas were cultured in normoxia, hypoxia, hypoxia/reoxygenation andCoCl2. AQP4 expression was confirmed by RT-PCR and western blot. Insilico analysis of the AQP4 promotor region was used to identify putativehypoxia responsive elements sites. AQP4 degradation was studied in thepresence of MG-132 or NH4Cl, proteosomal and lysosomal inhibitors,respectively.Results: We found that AQP4 protein expression was weakly detectable inpreeclamptic placentas, but its mRNA was elevated compared to that ofnormal placentas.In normal explants cultured in hypoxia, AQP4 mRNA and protein wereincreased but decreased following reoxygenation. Moreover, incubationwith CoCl2, that stabilizes hypoxia inducible factor 1α (HIF-1α) alsoincreased AQP4 levels. Finally, the in silico analysis showed threeputative binding sites for HIF-1α in AQP4 promotor.Conclusions: Our results propose that oxygen may regulate AQP4 expressionin human placenta, possibly through HIF-1α. Therefore, the decrease ofthis protein toward the end of gestation, consistent with changes in HIF-1α, suggests that AQP4 might have a crucial role during placentation.Thus, the abnormal expression of AQP4 might be involved in the etiologyof preeclampsia.