Differential Regulation of Glucose Transporters Mediated by CRH Receptor Type 1 and Type 2 in Human Placental Trophoblasts

Abstract

Glucose transport across the placenta is mediated by glucose transporters (GLUT), which is critical for normal development and survival of the fetus. Regulatory mechanisms of GLUT in placenta have not been elucidated. Placental CRH has been implicated to play a key role in the control of fetal growth and development. We hypothesized that CRH, produced locally in placenta, could act to modulate GLUT in placenta. To investigate this, we obtained human placentas from uncomplicated term pregnancies and isolated and cultured trophoblast cells. GLUT1 and GLUT3 expressions in placenta were determined, and effects of CRH on GLUT1 and GLUT3 were examined. GLUT1 and GLUT3 were identified in placental villous syncytiotrophoblasts and the endothelium of vessels. Treatment of cultured placental trophoblasts with CRH resulted in an increase in GLUT1 expression while a decrease in GLUT3 expression in a dose-dependent manner. Cells treated with either CRH antibody or nonselective CRH receptor (CRH-R) antagonist astressin showed a decrease in GLUT1 and an increase in GLUT3 expression. CRH-R1 antagonist antalarmin decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 antagonist astressin2b increased the expression of both GLUT1 and GLUT3. Knockdown of CRH-R1 decreased GLUT1 expression while increased GLUT3 expression. CRH-R2 knockdown caused an increase in both GLUT1 and GLUT3 expression. Our data suggest that, in placenta, CRH produced locally regulates GLUT1 and GLUT3 expression, CRHR1 and CRHR2-mediated differential regulation of GLUT1 and GLUT3 expression. Placental CRH may regulate the growth of fetus and placenta by modulating the expression of GLUT in placenta during pregnancy.

Second-trimester amniotic fluid corticotropin-releasing hormone and urocortin in relation to maternal stress and fetal growth in human pregnancy

“…Similarly, pregnant women, who are exposed to a prolonged period without food intake of more than 13 hours, exhibit higher plasma CRH levels compared to unexposed pregnant women (Hermann, Siega-Riz, Hobel, Aurora, & Dunkel-Schetter, 2001). It is interesting to note that in humans, placental CRH complexly regulates the expression of glucose transporter proteins and thus, glucose availability for fetal growth (Gao et al, 2012). Our finding of a positive correlation between second-trimester CRH and fetal catch-up growth is in line with these observations, contributes to the existing literature, and encourages further research along this path.…”

Regulation of Estradiol and Progesterone Production by CRH-R1 and -R2 Is through Divergent Signaling Pathways in Cultured Human Placental Trophoblasts

“…CRH-R1 and CRH-R2 have been found to trigger similar effects but sometimes opposite actions in various tissues. For instance, CRH-R1 and CRH-R2 exert opposite effect on prostaglandin production (31) and glucose transporter-1 but similar effect on glucose transporter-3 in placental trophoblasts (33). The present study demonstrated that CRH-R1 and CRH-R2 exhibited similar effects on E 2 and P 4 production in placental trophoblasts.…”

“…The following siRNA (sense, 5Ј-UUCUCCGAACGU GUCACGUTT-3Ј; antisense, 5Ј-ACGUGACACGUUCGGAGA ATT-3Ј), without homology to any known human mRNA sequences in the National Center for Biotechnology Information RefSeq database (Bethesda, MD), was used as a negative control. The cultured placental cells were transfected with siRNA-CRH-R1, siRNA-CRH-R2, and negative control siRNA using Lipofectamine 2000 (Invitrogen) as described previously (33). E 2 and P 4 assay E 2 and P 4 were assayed using commercially available RIA kits (Shanghai Institute of Biological Product, Shanghai, China).…”

Placental regulation of fetal nutrient supply

“…Moreover, GLUT-3 is present in the endothelial walls of umbilical arteries and recently it has been described also in placental syncytial microvillous membrane [3]. GLUT-3 shows high expression in placenta early in gestation, decreasing at the end of pregnancy [4].…”

“…In fact, GLUT-3 mutations cause early pregnancy loss and fetal growth restriction [5]. The different expression of GLUT-3 in placenta along gestation has been proposed to be associated with the local changes of CRH synthesis by the placenta [3], although other mechanisms could be also implicated. Interestingly, brain and placental tissue both are dependent upon these two glucose transporter (GLUT) isoforms GLUT-1 and GLUT-3 for glucose uptake, which are not insulin responsive.…”