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21: Novel insights into the mechanisms responsible for the up-regulation of the soluble receptor for advanced glycation end-products (sRAGE) in severe preeclampsia (sPE)

      Objective

      Activation of the pattern recognition cell surface receptor, RAGE, plays a key role in mediating oxidative and inflammatory cellular injury. sRAGE is a pleiotropic endogenous RAGE antagonist generated either by alternative splicing of RAGE mRNA (endogenous secretory RAGE: esRAGE) or by cleavage of the extracellular domain of the receptor. Our aim was to provide insight into the mechanisms responsible for the increased systemic and amniotic fluid (AF) levels of total sRAGE observed in sPE.

      Study Design

      In a case-control study we analyzed maternal serum samples from 81 singleton pregnancies grouped as: i) sPE (n=37, GA median [IQR]: 30 [27-32] wks); ii) healthy pregnancies delivered at term (CRL, n=31, GA: 30 [26-32] wks); iii) chronic hypertension (crHTN, n=13, GA: 32 [28-35] wks). There was no significant GA difference among groups at enrollment. AF was retrieved from 24 sPE women at the time of surgical delivery. For comparison we used 24 GA-matched AF samples from women without AF infection who delivered at term. Total sRAGE and esRAGE were measured by specific ELISAs. Placental villous tissue and amniochorion from 10 sPE cases and 10 GA-matched women with idiopathic preterm birth were obtained at delivery. Real-time qPCR was used to evaluate mRNA expression of the full-length RAGE and esRAGE.

      Results

      1) sPE women had significantly higher maternal serum total sRAGE and esRAGE compared to CRLs and crHTN even after correction for hematocrit (P<0.001); 2) AF total sRAGE and esRAGE levels were elevated in sPE (P<0.001); 3) In CRLs, the contribution of esRAGE to total sRAGE was higher in blood compared to AF (25% vs. 15%, P<0.001), a proportion that further increased in sPE; 4) Relative to full-length RAGE receptor, sPE women had a significant elevation in esRAGE transcript in amniochorion (P=0.032) but not placental villous tissue (P=0.975).

      Conclusions

      High maternal serum and AF esRAGE levels paralleled by elevated esRAGE expression in amniochorion implies that transcription plays a critical role in modulating the activity of the RAGE system in sPE.