Expression of Enzymes Regulating Placental Ammonia Homeostasis in Human Fetal Growth Restricted Pregnancies

Abstract 

Functional placental insufficiency results in impaired feto-placental exchange, and subsequently in fetal growth restriction (FGR). We hypothesized that reductions in placental amino acid transporter activities in FGR pregnancies may be accompanied by abnormal expression of placental ammonia-handling enzymes. Term placentas were obtained from growth restricted (N=11) and normal (N=17) human pregnancies, and examined for glutamate dehydrogenase (GDH), glutamine synthetase (GS) and glutaminase (GA) mRNA and protein expression. Northern and Western blots were normalized on human actin mRNA and protein expression. For GA, the presence of mRNA coding the kidney isoform, and the absence of mRNA coding the liver isoform of the enzyme were demonstrated in the human placenta. In FGR pregnancies, placental expression of GDH mRNA was reduced (P<0.05) compared to normal pregnancies (1.576±0.144 vs. 2.092±0.177, respectively; mean±SE), whereas GS and GA mRNA expression was not different between the two types of pregnancy. GDH protein expression were also reduced (P<0.05) in FGR placentas compared to normal placentas (1.055±0.079 vs. 1.322±0.053, respectively; mean±SE). The GS and GA protein expression was not different in FGR pregnancies. Our data indicate that in cases of FGR, glutamate-to-oxoglutarate transformation in the placenta is limited, yet glutamine synthesis from and decomposition to glutamate seems to be preserved. This may reflect down-regulation of GDH in response to decreased fetal liver output and reduced umbilical artery glutamate concentrations in human FGR pregnancies.

Keywords: Ammonia, Fetal growth restriction, Glutamate dehydrogenase, Glutaminase, Glutamine synthetase, Placenta