The reduction in FOXA2 activity during lung development in fetuses from diabetic rat mothers is reversed by Akt inhibition.

Hyperglycemia during pregnancy is associated with fetal lung development disorders and surfactant protein (SP) deficiency. Here, we examined the role of FOXA2 and Akt signaling in fetal lung development during diabetic pregnancy. Sprague-Dawley rats were injected with streptozocin (STZ) during pregnancy to induce diabetes (DM). DM-exposed fetal lungs exhibited reduced numbers of alveoli, irregularities in the appearance and thickness of the alveolar septum, increased levels of glycogen and lipids in type II alveolar epithelial cells, fewer microvilli and mature lamellar bodies, and swollen mitochondria. SP-B and SP-C in DM amniotic fluid and DM lungs were lower than in the control group (P < 0.05). DM lung nuclear FOXA2 was lower compared with the control group (P < 0.05), but p-FOXA2 was higher (P < 0.05). In murine lung epithelial (MLE) 12 cells, p-AKT levels were increased by high glucose/insulin, but decreased by the Akt inhibitor MK2206 (P < 0.05). Expression of nuclear FOXA2 was increased by MK2206 compared with the high glucose/insulin group (P < 0.05). These results suggest that maternal diabetes induces fetal lung FOXA2 phosphorylation through the Akt pathway, and also affects the maturation of alveolar epithelial cells and reduces levels of SP-B and SP-C in the fetal lungs. An Akt inhibitor reversed the changes in SP expression in vitro.