Accumulation of Advanced Glycation End Products in Women with Preeclampsia: Possible Involvement of Placental Oxidative and Nitrative Stress
Introduction
Advanced glycation end products (AGEs) have reactive, cross-linking molecules that are formed from the non-enzymatical glycation of reducing sugars and proteins, lipids, and nucleic acids [1], [2], [3], [4]. AGEs accumulate during natural ageing and are also greatly augmented in disorders such as diabetes, renal failure, and Alzheimer's disease. Plasma or serum AGE levels are high in patients with hyperglycemia and/or oxidative stress such as diabetes, rheumatoid arthritis, systemic lupus erythematosus (SLE), renal insufficiency, or cigarette smokers [5], [6], [7], [8], [9], [10], [11], [12].
The well studied cell surface receptor for AGE, namely RAGE, is a multiligand member of the immunoglobulin superfamily [4], [13], [14], [15], [16]. AGEs may cause tissue injury both directly through phenomena such as trapping and cross-linking and indirectly by binding to specific receptors for RAGE [9], [11], [12]. Interaction of AGEs with RAGE can lead to the generation of oxidative stress, production of growth factors and cytokines, chronic inflammatory responses, and cellular and vascular dysfunction [16], [17], [18].
AGEs are known to activate glial cells to produce nitric oxide (NO) and superoxide, which finally lead to neuronal cell death in the substantia nigra in Parkinson's disease [19]. We reported that AGEs stimulate secretion of chemokines such as macrophage inflammatory protein (MIP)-1α and MIP-1β, induce apoptosis, and suppress the secretion of human chorionic gonadotropin in isolated human first-trimester trophoblasts [20]. We also reported that inhibitors of NO synthases or the NF-κB pathway suppress these effects of AGEs [20]. This suggests that reactive nitrogen species as well as reactive oxygen species contribute to AGE-mediated cytotoxicity in the human placenta.
Preeclampsia, which is one of the most significant causes of maternal and perinatal morbidity and mortality [21], [22], is characterized by systemic and uteroplacental vascular dysfunction [23], [24], [25]. Oxidative stress in the placenta as well as the maternal vascular system has been implicated as pathophysiological features of preeclampsia [26], [27]. Nitrotyrosine residues, which are a marker of the prooxidant peroxynitrite formation and action, are found in the placenta from women with preeclampsia, chorioamnionitis, or placental abruption, indicating oxidative stress [28], [29]. 4-Hydroxy-2-nonenal (4-HNE)-modified proteins, which are major propagation products of lipid peroxidation, have also been reported to accumulate to a greater extent in preeclamptic placenta than in normal placenta [30], [31] although this is still controversial [27], [32].
Although AGE–RAGE interaction is implicated in oxidative stress associated with inflammatory responses, AGE formation in preeclamptic women has never been published. In the present study, we examined the accumulation of AGEs in serum and placenta from preeclamptic women. We also studied other various biomarkers for oxidative stress in preeclamptic placenta, such as nitroguanosine, 4-HNE, and 8-hydroxy-2′-deoxyguanosine (8-OHdG).
Section snippets
Patients
Twenty pregnant women and 10 healthy non-pregnant women were recruited for this study. Informed consent was obtained from each woman and the protocol for this study was approved by the local institutional review board. All women were non-smokers, non-diabetic, and had no family history of premature vascular diseases. We excluded pregnant women with PROM, chorioamnionitis, or clinical infection from this study to avoid influence of infection. Preeclampsia was defined as a blood pressure greater
Serum level of AGEs
AGEs were detected in all subjects. There was no significant difference in the serum level of AGEs between healthy non-pregnant women (100 ± 25.2%, mean ± S.D.) and healthy pregnant women (116.6 ± 31.6%). Preeclamptic women (157.8 ± 51.9%) had a significantly higher mean level of AGEs as compared with healthy non-pregnant women (p < 0.005) or healthy pregnant women (p < 0.05) as shown in Figure 1.
Western blot analysis of AGEs and RAGE in placenta
Western blot analysis showed that two major bands corresponding to AGEs were detected in the homogenates of
Discussion
In the present study, we observed increased mean levels of serum AGEs from the preeclamptic women as compared with the healthy non-pregnant women or the healthy pregnant women. We also observed that the intensity of immunostaining of AGEs in the placentas from preeclamptic women was greater than that in the placentas from healthy women. The levels of AGEs in the placenta from the preeclamptic women were also significantly higher than those in the placenta from the healthy women. Gestational age
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2019, American Journal of Obstetrics and GynecologyCitation Excerpt :Other investigators found that accumulation of advanced oxidation protein products drives the expression of soluble sFlt-1 in trophoblast cells.41,42 Likewise, accumulation of advanced glycation end products in extravillous trophoblast and endothelial cells has also been linked to increased reactive oxygen species production and upregulation of sFlt-1 expression.43,44 Compelling experimental evidence indicates that endotheliosis in the systemic, renal, cerebral, or hepatic circulations perturbs the balance of endothelium-derived vasodilators (eg, nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor) and vasoconstrictors (eg, endothelin-1 and thromboxan-A2), leading to increased vasoconstriction, hypertension, and other manifestation of preeclampsia.45