Increased O -Linked N-Acetylglucosamine Modification of NF- ΚB and Augmented Cytokine Production in the Placentas from Hyperglycemic Rats

AbstractInflammation as a result of NF- κB activation may result from the classical (canonical) pathway, with disconnection of the IκB inhibitor and subsequent nuclear translocation or, alternatively, by post-translational modifications of modulatory proteins or NF-κB subunits (non-canonical pathway). We hypothesized that hyperglycemia -induced increased glycosylation withO-linked N-acetylglucosamine (O-GlcNAc) of NF- κB in placental tissue leads to augmented production of pro-inflammatory cytokines, culminating in placental dysfunction and fetal restriction growth. Single injections of streptozotocin (40 mg/kg) or vehicle were used to induce hyperglycemia or normoglycemia, respectively, in female Wistar rats. After 3 days, rats were mated and pregnancy confirmed. Placental tissue was collected at 21 days of pregnancy. Placental expression of p65 subunit was similar between groups. However, nuclear translocation of p65 subunit, showing greater activation of NF-κB, was increased in the hyperglycemic gro up. Reduced expression of IκB and increased expression of phosphorylated IκBSer32 were observed in the placenta from hyperglycemic rats, demonstrating increased classical NF- κB activation. Augmented modification ofO-GlcNAc-modified proteins was found in the placenta from hyperglycemic rats and p65 subunit was a keyO-GlcNAc target, as demonstrated by immunoprecipitation. Tumor necrosis factor-alpha (TNF- α) and interleukin-6 (IL-6) expressions were increased in the ...
Source: Inflammation - Category: Allergy & Immunology Source Type: research