Identification of relevant pathogenic pathways that may be responsible for the increased morbidity and mortality of fetuses with IUGR is critical. Recent advances have provided an improved understanding of the mechanisms of chronic cellular injury following engagement of RAGE (membrane cell receptor) and soluble RAGE (sRAGE, competitive inhibitor) in complex diseases such as preterm birth (PTB) and preeclampsia (PE). The objective of this study was to investigate the fetal serum levels of total sRAGE and endogenous secretory RAGE (esRAGE, alternative spliced RAGE isoform) in fetuses with IUGR and correlate with neonatal death as the adverse outcome.
In a case-control study, cord blood serum sRAGE and esRAGE were measured by specific immunoassays in 84 consecutive preterm singleton newborns in the following groups: (i) idiopathic PTB (iPTB, n=27, GA: median [IQR] 31 [30-32] wks); (ii) severe PE (sPE) without IUGR (n=23, GA: 31 [28-32] wks); (iii) sPE+IUGR (n=22, GA: 28 [25-33] wks); (iv) idiopathic IUGR (n=12, GA: 29 [27-32] wks). Established criteria were used to define iPTB, sPE, IUGR (<10%) and abnormal Dopplers.
There was a significant difference in birthweight (P<0.001) but not GA among groups; 2)
IUGR fetuses had lower total sRAGE levels independent of sPE (2-way ANOVA P<0.001, Figure
The contribution of esRAGE to total sRAGE was similar (∼40%) with no differences in esRAGE levels between groups; 4)
sRAGE and esRAGE levels were not impacted by GA, Doppler indices or acid-base status at delivery; 5)
IUGR newborns who died (n=9) had significantly lower total sRAGE (P<0.05) at birth.
This study demonstrates involvement of RAGE pathway in the pathogenesis of IUGR and related neonatal death. Similar levels of esRAGE suggest that the transcriptional mechanism responsible for sRAGE production remains intact. The cause for sRAGE deficiency in IUGR fetuses may be either lack of post-translational RAGE processing or excessive consumption by RAGE ligands.
© 2011 Mosby, Inc. Published by Elsevier Inc. All rights reserved.