Role of adiponectin on antioxidant profile: evaluation during healthy and hypertensive disorders of pregnancy

Abstract

The study of adipokines and oxidative stress has aided in understanding pre-eclampsia physiopathology. Therefore, our group aimed to evaluate the correlation between the adipokines (adiponectin and leptin) and the oxidative stress marker malondialdehyde–thiobarbituric acid reactive substances (MDA-TBARS) and antioxidant activity of plasma [ferric reducing ability of plasma (FRAP)] in healthy pregnant women and patients with gestational hypertension and pre-eclampsia. We found a significant negative correlation between MDA-TBARS and adiponectin (r = –0.40, p = 0.0042), suggesting a relationship between antioxidant levels and this adipokine in healthy pregnancies which is altered in patients with gestational hypertension or pre-eclampsia.

Keywords:

• Adipokines
• gestational hypertension
• oxidative stress
• pre-eclampsia
• pregnancy

Introduction

Different mechanisms have been proposed to cause pre-eclampsia (PE), including the involvement of an imbalance among antiangiogenic and proangiogenic factors secreted by the placenta,[1] the action of adipokines, such as adiponectin and leptin,[2,3] and oxidative stress.[4,5] Adiponectin has anti-inflammatory, antiatherogenic, insulin-sensitizing properties [1,6] in addition to carrying out antioxidant and angiogenic functions on vascular physiology.[7] Leptin is also involved in various physiological processes including regulation of endocrine function, inflammation, immune response, reproduction and angiogenesis.[6]

Oxidative stress is an important process for normal physiological functions and placental development.[8] However, in PE, this process is intensified and the presence of placental ischaemia/hypoxia results in oxidative stress with consequent endothelial dysfunction and systemic vasoconstriction.[4,5]

Although the antioxidant actions of adiponectin have been demonstrated in multiple studies,[9,10] to our knowledge no prior study has investigated the relationship between adipokines and markers of oxidative stress in pregnant patients with PE. Therefore, the aims of the present study were to evaluate the correlation between the adipokines (adiponectin and leptin) and markers of oxidative stress [malondialdehyde–thiobarbituric acid reactive substances (MDA-TBARS)] and antioxidant activity of plasma [ferric reducing ability of plasma (FRAP)] in healthy pregnant (HP) patients and patients with hypertensive disorders of pregnancy [gestational hypertension (GH) and PE].

Materials and methods

Approval for the use of human subjects was obtained from the Institutional Review Board at the Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil, and informed consent was obtained from volunteers. In total, 108 pregnant patients were enrolled in the Department of Obstetrics and Gynecology, University Hospital of the Faculty of Medicine of Ribeirao Preto. Of them, 50 were HP women with uncomplicated pregnancies, 27 had GH and 31 had PE.

Biomarkers’ plasma concentrations were measured using the commercially available enzyme-linked immunosorbent assay (ELISA) kits Human Adiponectin EZHADP-61K and Human Leptin EZHL-80SK (Millipore; St. Charles, MO, USA), according to the manufacturer’s instructions. Lipid peroxidation was assessed by measurement of MDA-TBARS, using the method described by Buege and Aust.[11] Antioxidant status was evaluated by the assessment of FRAP, using the method described by Benzie and Strain.[12]

Clinical parameters and biomarker concentrations are shown as mean ± SD. The groups were compared by analysis of variance (ANOVA) (parametric data) and the chi-squared test (nominal data). Biomarkers were correlated using the Pearson test. A probability value < 0.05 was considered statistically significant.

Results

Clinical characteristics were similar (p > 0.05) in the three groups (HP, GH and PE) studied: maternal age (25.4 ± 6.3, 25.9 ± 6.6 and 27.0 ± 7.2 years, respectively) and body mass index (22.8 ± 3.0, 24.0 ± 3.4 and 23.3 ± 3.5, respectively). However, differences were found between gestational age at sampling and at delivery (both p < 0.001, HP vs PE and GH vs PE), systolic (p < 0.001 between all groups) and diastolic (p < 0.001, HP vs PE and GH vs PE) blood pressure, proteinuria (p < 0.035, GH vs PE) and newborn weight (p < 0.001, HP vs PE and GH vs PE).

Plasma levels of adiponectin (17.7 ± 4.7, 18.3 ± 5.5 and 20.2 ± 8.8 ng/ml) and leptin (21.3 ± 12.2, 26.0 ± 21.8 and 28.7 ± 17.4 ng/ml) were similar in the HP, GH and PE groups, respectively. Plasma antioxidant status (FRAP) showed gradual elevations (502.8 ± 116.7, 535.2 ± 115.1 and 598.4 ± 128.8 μM) between the HP, GH and PE groups, with a significant difference (p < 0.01) between the HP and PE groups. However, the plasma levels of MDA-TBARS (4.7 ± 1.7, 4.5 ± 1.5 and 4.7 ± 1.6 nM) were similar (p > 0.05) between the groups.

Table 1 shows the correlations among adipokines and oxidative stress markers in the three groups. We found significant negative correlations between MDA-TBARS and adiponectin in HP, but not in the GH and PE groups. Others correlations did not show statistically significant differences.

Table 1. Correlations between adipokines and oxidative stress markers in pregnant groups.

Biomarker	HP		GH		PE
	MDA (nM)	FRAP (μM)	MDA (nM)	FRAP (μM)	MDA (nM)	FRAP (μM)
Adiponectin (ng/ml)	r = –0.40; p = 0.0042*	r = –0.08; p = 0.57	r = –0.08; p = 0.70	r = –0.11; p = 0.58	r = 0.03; p = 0.87	r = –0.10; p = 0.61
Leptin (ng/ml)	r = –0.08; p = 0.57	r = 0.07; p = 0.61	r = 0.03; p = 0.87	r = 0.02; p = 0.93	r = –0.18; p = 0.34	r = 0.14; p = 0.41

HP, healthy pregnant; GH, gestational hypertension; PE, pre-eclampsia; MDA, malondialdehyde; FRAP, ferric reducing ability of plasma.

* p < 0.05 vs healthy pregnant.

Discussion

Our study is the first to assess the correlation among adipokines and oxidative stress markers in hypertensive disorders of pregnancy. The negative correlation observed between circulating adiponectin levels and the MDA-TBARS biomarker suggests an important role of adiponectin on the antioxidant profile in HP woman, which is lost in pregnancies presenting with hypertensive disorders. Furthermore, elevations in FRAP levels suggest the presence of an antioxidant response during hypertensive disorders of pregnancy, supposedly due to adiponectin, but the action of this adipokine seems to be limited.

Vaiopoulos et al. [13] proposed a signalling scheme seeking to improve our understanding of the role of adiponectin in vascular physiology. This model suggests that the interaction of adiponectin with the receptor R1 may activate the cyclic adenosine monophosphate pathway and result in the reduction of reactive oxygen species. Lautamäki et al. [14] observed an inverse association between adiponectin and an oxidative stress marker, oxidized low-density lipoprotein, in patients with type 2 diabetes mellitus and ischaemic coronary artery disease, suggesting antioxidant effects of adiponectin. Moreover, Barazzoni et al. [9] evaluated patients with chronic kidney disease and observed a link between increased oxidative stress and reduced levels of adiponectin expression in adipose tissue, suggesting that in patients with advanced renal failure the causes of oxidative stress are multifactorial. In addition, Indulekha et al. [10] found in Asian diabetic patients a significant negative association between TBARS and adiponectin (high molecular weight fraction), corroborating our findings.

Longitudinal studies have observed changes in adipokine concentrations during the normal pregnancy course, associating [15] or not [16] the levels with body mass index and suggesting implications of gestational period on circulating levels. On the other hand, published studies on adiponectin and leptin levels during PE are controversial, including reports of elevated levels [2,17] and reduced levels,[3,18] suggesting the involvement of these molecules in the pathophysiology of the disease. Retnakaran and Retnakaran [1] reinforce that the evidence in PE suggests compensatory effects of the adiponectin in response to vascular injury.

Recently, Kurlak et al. [19] evaluated the oxidative stress profile (MDA and FRAP) in PE and GH, including pregnancies at term and preterm. These not observed differ between hypertensive states but appear to distinguish between recently pregnant and non-pregnant states, suggesting that pregnancy may alter vascular integrity. Elevations in FRAP and similar TBARS levels in the three groups (HP, GH and PE) reproduce the findings of Gomes et al.[20]

In conclusion, our data suggest antioxidant effects of adiponectin. Hypertensive disorders of pregnancy are complex conditions that involve different mechanisms, including the actions of adipokines to reduce the effects of oxidative stress. Our findings reinforce the role that these molecules play in the pathophysiology of hypertensive disorders of pregnancy and provide a basis for completing broader studies.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This research was supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP-Brazil).