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264: In severe preeclampsia, activation of the receptor for advanced glycation end-products (RAGE) system occurs independent of antigenic N-carboxymethyl-lysine modified proteins

      Objective

      Severe preeclampsia (sPE) is characterized by RAGE system activation, which leads to inflammation, oxidative stress and endothelial injury. The putative stimulus remains unknown. One candidate is the antigenic N-carboxymethyl-lysine (CML), an advanced glycation end-product (AGE) formed by the nonenzymatic glycation of proteins. This study was conducted to determine if CML and CML auto-antibodies may be responsible for activation of the RAGE system in women with sPE.

      Study Design

      In a case control study we analyzed time-matched samples of blood and urine from 118 women with either sPE (n=79, GA: 31 [22-36] wks) or uncomplicated pregnancies delivered at term (CRL n=39, GA: 30 [21-34] wks). Circulating soluble RAGE (sRAGE) served as a marker of RAGE activation. Levels of CML, CML auto-antibodies and sRAGE were assessed by sensitive and specific immunoassays. Urine analytes were normalized to creatinine. In addition, we employed immunolocalization for CML in placental tissue sections from women with sPE (n=6). We used as control placental tissues from GA matched women with idiopathic preterm birth and no histological chorioamnionitis (n= 6).

      Results

      1) In women with sPE, increased circulating levels of sRAGE proved RAGE system activation (sPE vs. CRL, P<0.001); 2) CML and CML auto-antibodies were detectable in blood and urine of healthy CRLs, but no differences were seen in comparison to sPE; 3) There was no correlation between circulating and urinary CML or CML auto-antibodies with sRAGE; 4) Though clumpy deposits of CML immunoreactive proteins in decidua, villous stroma, and maternal vascular spaces were seen, there were no discernable differences among the groups.

      Conclusion

      We provide evidence that RAGE system activation in sPE may occur through a pathway independent of AGEs.