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Cultured trophoblasts are salt-sensitive with Na+ and Cl- transporters differentially expressed in placenta and kidney of rats upon salt exposure
06 April 2017 (online)
Previously, we and other demonstrated that in pregnancy enhanced intake of NaCl does lower maternal blood pressure and improves pregnancy outcome for yet unknown reasons. As non-renal targets respond to Na+ exposure such as dendritic skin cells, we hypothesized that trophoblasts react upon being Na+-challenged with favourable responses.
The human choriocarcinoma cell lines BeWo and JEG-3 were coincubated with different Na+ concentrations in the absence or presence of forskolin (2 × 10-5M) and aldosterone (10-7M). Non-pregnant and pregnant rats were exposed to either normal, low (LS), high (HS) or high/low (HS/LS) Na+ intake, sacrificed at day 20 and placentae and kidneys were frozen and stored at -80 °C. TaqMan PCR was applied to the tonicity element binding protein (TonEBP), the angiogenic signals VEGF-C and PlGF as well as to transporters related to Na+ and Cl- transport pendrin, ENaC, NHE1, NKCC1 and ATP1A1. Relative quantification was performed and results normalised to several housekeeping genes.
Following NaCl incubation TonEBP expression rose early (p < 0.01-< 0.001), much less than chronically. In placental tissue, LS while in pregnant kidney medulla HS and in the non-pregnant cortex only HS/LS led to a higher expression. VEGF-C and PlGF signaling was affected in culture. In term placentae VEGF-C expression rose (p < 0.01) with HS/LS diet. Renal VEGF-C and PlGF levels were rather low and stable. Pendrin is upregulated early, but not late upon NaCl exposure (p < 0.01-p < 0.001). The EnaC α-subunit is down-regulated early and late in BeWo, yet upregulated in JEG-3 cells with higher Na+, while the γ-subunit is clearly upregulated in both (p < 0.05-p < 0.001). The other channels are less regulated on the expression level. Exposure to HS enhanced placental pendrin, to LS EnaC α- and γ-subunit. Exposure of kidneys to pregnancy conditions did alter transporter expression only moderately, yet placental responses were reverse. The remaining investigated transporters were relatively unaffected.
This study is the first to show that Na+ effects placental and trophoblast tonicity responses and suggests upon a specific trophoblast and placental regulation of Na and Cl transporters different to the kidneys a placenta Na+ sensitivity. These results suggest a placental environmental link, yet the members of the signaling chain still have to be further addressed.