Placental miR-1301 is dysregulated in early-onset preeclampsia and inversely correlated with maternal circulating leptin
Introduction
Preeclampsia is a pregnancy-specific disorder affecting 3–10% of all pregnancies and a significant cause of maternal and neonatal morbidity and mortality, especially dangerous for many women and their offspring in developing economies. Several studies have suggested that early- and late-onset PE are two distinct subtypes of the disease but with overlapping features [1], [2]. While early-onset is regarded to often represent a more severe type of the disease with a dysfunctional placentation origin, late-onset is less often associated with fetal growth restriction and remote maternal cardiovascular disease risk [3]. Also, early- and late-onset PE have been shown to have distinct placental genetic profiles [4], but distinct miRNA profiles from placental tissues for these two important categories of preeclampsia have to our knowledge not been identified. Placenta is also among the tissues with the highest concentration of miRNA, suggesting an important role for miRNA in this tissue and in pregnancy [5].
MicroRNAs (miRNAs) are short (∼22 nucleotides) noncoding RNAs that play a critical role in posttranscriptional gene regulation by pairing with the 3' UTRs of protein-coding gene mRNAs. miRNA binding generally results in gene silencing, either by translational repression or target degradation. miRNAs are important for fine-tuning of gene expression in diverse developmental and physiological settings. Typically, several miRNAs regulate one mRNA and one miRNA regulate several mRNAs [6]. Consistent with this notion, a growing number of pathological processes are associated with mis-expression of certain types of miRNAs. The importance of these miRNAs in regulating placental function has only recently been uncovered. miRNA-mediated regulation in pregnancy remains poorly investigated although several independent processes associated with placental development have been shown to be regulated by miRNAs [7].
Pregnancy is a state of maternal hyperlipidemia, as compared to non-pregnancy. The hyperlipidemia is even more exaggerated in a pregnancy complicated by preeclampsia. Excessive generalized maternal (vascular) inflammation, caused by placental oxidative stress and dysfunction, with release of placenta-associated factors, has been proposed to mediate this excessive hyperlipidemia of preeclampsia [8].
The three adipokines leptin, resistin and adiponectin have been shown to be expressed not only in adipose tissue but also in placenta [9]. Leptin is a key hormone in the regulation of energy intake and energy expenditure and is the most studied of these three adipokines in pregnancy [9]. Placental leptin gene (LEP) expression is elevated in preeclampsia, but maternal circulating leptin levels are highly elevated even before the onset of clinical signs of disease [10], [11]. In addition to its involvement in energy homeostasis, increasing evidence suggest that leptin is a proinflammatory factor [12]. Increased leptin has also been speculated to be involved in the pathophysiology of preeclampsia [9], by representing an inflammatory stimulus [8] or stimulating hypertension and proteinuria by other mechanisms [13]. Although many studies have shown a strongly increased concentration of circulating leptin and placental upregulation of LEP expression during pregnancy [14], [15], [16], current knowledge on how placental LEP expression is regulated is limited. The placental and adipose form of LEP mRNA is the same, but placental-specific enhancers have been identified. Both hypoxia and insulin can probably induce expression of leptin in placenta [17].
The aim of this study was to investigate the global expression of miRNAs in early- and late-onset PE compared to normal pregnancies without complications (named controls). Further, we wanted to increase the understanding of how miRNAs could contribute to the regulation of the most investigated adipokines during pregnancy, by studying if some miRNAs were inversely associated with their respective predicted adipokine targets.
Section snippets
Patient selection
Placental tissue and maternal blood samples were obtained from an ongoing biobank recruitment of patients at Oslo University Hospital, Norway. Women with a singleton pregnancy delivered by elective caesarean section were included in this study (n = 85). This included 29 women with uncomplicated pregnancy (controls) delivered at term (week 37–41), 29 with preeclamptic pregnancies delivered prior to week 34 (early-onset PE), as well as 27 preeclamptic pregnancies delivering after or including
Clinical characteristics
The clinical characteristics of the preeclamptic and control groups are shown in Supplementary Table 3. There was no statistically significant difference in systolic or diastolic blood pressure <week 20 between the three patient study groups. Further, intrauterine growth restriction complicated 6 pregnancies, 3 in the early-onset PE group and 3 in the late-onset PE group. There was a significantly higher maternal median BMI at delivery (weight (kg)/height (m)2) in the early-onset PE group
Discussion
It has been suggested that early- and late-onset preeclampsia (for example defined as deliveries before week 34 and deliveries from week 34 and onwards) have different predominating etiologies, but that more research is needed to get a clear picture of this [1]. Still, no sharp line can be drawn between early- and late-onset preeclampsia with regard to the predominating presumed etiology (placental vs maternal) and there is probably a mix of these two forms present in most of PE, in line with
Authorship and conflicts of interest
All authors fulfill the authorship criteria as defined by the Vancouver agreement. All authors have read and approved the submission of the manuscript. There are no potential conflicts of interest and no products/companies are discussed in the article in which any author has an interest.
The manuscript (or any closely related research work) has not been published and is not being considered for publication elsewhere, in whole or in part, in any language, or as an abstract.
Acknowledgments
Sequencing was performed by the Norwegian Sequencing Centre, a national technology platform supported by the Functional Genomics and Infrastructure programs of the Research Council of Norway and the Southeastern Regional Health Authorities.
The authors thank Lise Levy at The Research Center for Obstetrics and Gynecology, Oslo University Hospital (led by ACS), for excellent patient recruitment as well as technical biobank and laboratory assistance. The authors thank the medical faculty at
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2020, Metabolism: Clinical and ExperimentalThe cross-talk between adipokines and miRNAs in health and obesity-mediated diseases
2019, Clinica Chimica ActaCitation Excerpt :The modulatory effects of miRNAs on adipokines are mediated by targeting the expression of adipokines and their receptors, as well as their related signaling pathways and functions. For example, miR-1301 is dysregulated in patients with early-onset preeclampsia and potentially plays a role in the regulation of leptin levels during pregnancy [132]. Several molecules exert anti-leptin effects through the up/downregulation of miRNA expression.