Involvement of Receptor for Advanced Glycation Endproducts in Hypertensive Disorders of Pregnancy.

Uchiyama Uchiyama,Sado Sado,Ota Ota,Itaya-Hironaka Itaya-Hironaka,Kobayashi Kobayashi,Yamauchi Yamauchi,Sakuramoto-Tsuchida Sakuramoto-Tsuchida,Naruse Naruse,Makino Makino,Akasaka Akasaka,Takasawa Takasawa

doi:10.3390/ijms20215462

Abstract

Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially life-threatening disease. Recently, PE/HDP has been considered to cause adipose tissue inflammation, but the detailed mechanism remains unknown. We exposed human primary cultured adipocytes with serum from PE/HDP and healthy controls for 24 h, and analyzed mRNA expression of several adipokines, cytokines, and ligands of the receptor for advanced glycation endproducts (RAGE). We found that the mRNA levels of interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), high mobility group box 1 (HMGB1), and RAGE were significantly increased by the addition of PE/HDP serum. Among RAGE ligands, advanced glycation endproducts (AGE) and HMGB1 increased mRNA levels of IL-6 and CCL2 in SW872 human adipocytes and mouse 3T3-L1 cells. The introduction of small interfering RNA for RAGE (siRAGE) into SW872 cells abolished the AGE- and HMGB1-induced up-regulation of IL-6 and CCL2. In addition, lipopolysaccharide (LPS), a ligand of RAGE, increased the expression of IL-6 and CCL2 and siRAGE attenuated the LPS-induced expression of IL-6 and CCL2. These results strongly suggest that the elevated AGE, HMGB1, and LPS in pregnant women up-regulate the expression of IL-6 and CCL2 via the RAGE system, leading to systemic inflammation such as PE/HDP.

Highlights

Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially lifethreatening disease appearing as a complication in about 2–12% of all pregnancies and associated with significant perinatal and maternal mortality [1,2]
We incubated primary cultured human adipocytes with sera from disease-free pregnant women or those from PE/HDP for 24 h, and the gene expression of IL-6, C motif chemokine ligand 2 (CCL2), tumor necrosis factor α (TNFα), leptin (LEP), adiponectin (ADIP), resistin (RETN), high mobility group box 1 (HMGB1), S100 Ca2+-Binding Protein B (S100B), and receptor for advanced glycation endproducts (RAGE) in the adipocytes was measured via real-time reverse transcriptase-polymerase chain reaction (RT-PCR)
Previous studies indicated that body mass index (BMI), anemia, lower education, maternal age, primiparity, multiple pregnancy, PE/HDP in previous pregnancy, gestational diabetes mellitus, preexisting hypertension, preexisting type 2 diabetes mellitus, preexisting urinary tract infection, and a family history of hypertension, type 2 diabetes mellitus, or PE/HDP are potential risk factors for PE/HDP [39,40]

Summary

Introduction

Preeclampsia/hypertensive disorders of pregnancy (PE/HDP) is a serious and potentially lifethreatening disease appearing as a complication in about 2–12% of all pregnancies and associated with significant perinatal and maternal mortality [1,2]. There is considerable evidence that maternal obesity, increased insulin resistance, inflammation, and aberrant fatty acid metabolism are involved in the pathogenesis of PE/HDP [4,5]. Shallow trophoblast invasion and inadequate artery remodeling in pregnancy may cause placental hypoperfusion, hypoxia, or ischemia, which play an important role in the pathogenesis of PE/HDP [15]. White adipose tissue secretes pro-inflammatory cytokines which contribute significantly to the chronic inflammatory state and metabolic complications of obesity [17]. It is plausible that similar disturbances in adipocyte function might contribute to the development of the clinical syndrome of PE/HDP, a state of inflammation and insulin resistance

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Conclusion