Elsevier

Placenta

Volume 27, Issues 2–3, February–March 2006, Pages 225-233
Placenta

Accumulation of Advanced Glycation End Products in Women with Preeclampsia: Possible Involvement of Placental Oxidative and Nitrative Stress

https://doi.org/10.1016/j.placenta.2005.02.016Get rights and content

Advanced glycation end products (AGEs) are known to cause oxidative damage in various cells by binding with its receptor, RAGE. We measured the serum level of AGEs and examined the AGEs, RAGE, and the other biomarkers of oxidative stress in the placentas from preeclamptic women.

Competitive ELISA was carried out to measure the AGEs in serum. Western blotting was performed to analyze AGEs and RAGE in the placenta. Immunohistochemical analyses were performed to examine the localization of AGEs, RAGE, and other biomarkers of oxidative stress in the placenta.

The mean level of serum AGEs in preeclamptic women was significantly higher than that in healthy non-pregnant women or healthy pregnant women. Western blotting revealed that the level of AGEs or RAGE in preeclamptic placenta was significantly higher than that in normal placenta. Immunohistochemical analyses showed that levels of nitrotyrosine and nitroguanosine, which are formed by reactive nitrogen species, in preeclamptic placenta were higher than those in normal placenta. Accumulation of 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine indicated enhanced oxidative modifications of lipids and DNA in preeclamptic placenta.

The AGE–RAGE system, which is upregulated in preeclampsia, is likely to be involved in the oxidative stress of preeclampsia.

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

References (54)

  • M. Nakatsuka et al.

    Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts

    Life Sci

    (2000)
  • A. Neumann et al.

    High molecular weight hyaluronic acid inhibits advanced glycation end product-induced NF-κB activation and cytokine expression

    FEBS Lett

    (1999)
  • A. Many et al.

    Invasive cytotrophoblasts manifest evidence of oxidative stress in preeclampsia

    Am J Pathol

    (2000)
  • J. Stanek et al.

    Nitrotyrosine immunostaining correlates with increased extracellular matrix: evidence of postplacental hypoxia

    Placenta

    (2001)
  • T. Sawa et al.

    Superoxide generation mediated by 8-nitroguanosine, a highly redox-active nucleic acid derivative

    Biochem Biophys Res Commun

    (2003)
  • L.L. Wu et al.

    Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics

    Clin Chim Acta

    (2004)
  • M. Brownlee et al.

    Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications

    N Engl J Med

    (1988)
  • H. Vlassara et al.

    Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling

    Science

    (1988)
  • M. Kirstein et al.

    Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging

    Proc Natl Acad Sci U S A

    (1990)
  • A.M. Schmidt et al.

    Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions

    Arterioscler Thromb

    (1994)
  • C. Cerami et al.

    Tobacco smoke is a source of toxic reactive glycation products

    Proc Natl Acad Sci U S A

    (1997)
  • J. Rodriguez-Garcia et al.

    Increased concentrations of serum pentosidine in rheumatoid arthritis

    Clin Chem

    (1998)
  • S. Ligier et al.

    A new antibody in rheumatoid arthritis targeting glycated IgG: IgM anti-IgG-AGE

    Br J Rheumatol

    (1998)
  • I.D. Nicholl et al.

    Advanced glycation end products and cigarette smoking

    Cell Mol Biol

    (1998)
  • A.M. Schmidt et al.

    Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis

    Circ Res

    (1999)
  • A.K. Mohamed et al.

    The role of oxidative stress and NF-κB activation in late diabetic complications

    Biofactors

    (1999)
  • R. Singh et al.

    Advanced glycation end-products: a review

    Diabetologia

    (2001)
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