Advanced glycation end-products change placental barrier function and tight junction in rats with gestational diabetes mellitus via the receptor for advanced glycation end products/nuclear factor-κB pathway

[摘要] The placenta plays an important role in nutrient transport to maintain the growth and development of theembryo. Gestational diabetes mellitus (GDM), the most common complication during pregnancy, highly affectsplacental function in late gestation. Advanced glycation end-products (AGEs), a complex and heterogeneous group ofcompounds engaged by the receptor for AGEs (RAGE), are closely associated with diabetes-related complications. Inthis study, AGEs induced a decrease in the expression of tight junction (TJ) proteins in BeWo cells and increased theparacellular permeability of trophoblast cells by regulating RAGE/NF-κB. Sprague-Dawley (SD) rats injected with100 mg/kg AGEs-rat serum albumin (RSA) via the tail vein from embryo day 2 were set as the placental barrierdysfunction model group (n = 10). The effect of AGEs on placental permeability was determined using the EvansBlue dye extravasation method. The ultrastructure of the placenta samples was observed by transmission electronmicroscopy. The effects of AGEs on the placenta were confirmed by treating rats with RAGE antagonist FPS-ZM1and soluble forms of RAGE (sRAGE). AGEs treatment increased placental permeability and disrupted the tightjunctions in pregnant rat placenta, but has no effect on blood glucose. The expression of TJ-related proteins,including ZO-1, Occludin, and Claudin 5, were downregulated after AGEs treatment. Further, AGEs treatmentincreased the expression of RAGE and nuclear factor-κB in the placenta of rats and upregulated the levels of vascularendothelial growth factor. The effects of AGEs on the placenta were blocked by RAGE antagonist FPS-ZM1 andsRAGE. This study demonstrates the mechanism underlying AGEs-induced disturbance in placental function inpregnant rats and highlights the potential of AGEs in the treatment of GDM.

[学科分类] 仪器

[关键词] Gestational diabetes mellitus;Advanced glycation end-products;RAGE- NF-κB;Placental barrier;Tight junction