Advanced glycation end products induce secretion of chemokines and apoptosis in human first trimester trophoblasts

Background: We studied the effects of advanced glycation end products (AGEs), which are known to accumulate in patients with diabetes, autoimmune diseases, or that smoke, on human trophoblasts. Methods: First trimester human chorionic villi of 6-10 week gestation were obtained. Expression and localization of the receptor for AGEs (RAGE) was examined by western blotting and immunohistochemistry. Macrophage inflammatory protein (MIP)-1α and MIP-1β, regulated upon activation, normal T-cell expressed and secreted (RANTES), and human chorionic gonadotropin (hCG) in culture medium were measured by ELISA. Trophoblastic apoptosis was evaluated by the Hoechst 33258 staining and the in situ nick end labeling technique. Results: RAGE was localized in trophoblasts. AGEs significantly stimulated secretion of both MIP-1α and MIP-1β from trophoblasts in a time- and dose-dependent manner. AGEs significantly induced apoptosis and reduced secretion of hCG. Increased secretions of MIP-1α and MIP-1β by AGEs were significantly suppressed by inhibitors of nitric oxide synthase (NOS) or nafamostat mesilate, a synthetic serine protease inhibitor and a suppressor of transcription factor, NF-κB activation. These agents also suppressed the effects of AGEs on hCG secretion and trophoblastic apoptosis. Conclusions: These AGE-mediated changes in trophoblasts may lead to impairment of implantation and placentation. NOS inhibitors or nafamostat mesilate may modify these effects.