Galectin-7 dysregulates renin-angiotensin-aldosterone and NADPH oxide synthase pathways in preeclampsia

Preeclampsia is a life-threatening disorder of pregnancy unique to humans. Worldwide, more than 4 million women develop preeclampsia each year [1], resulting in significant maternal and neonatal morbidity and mortality [1], [2], [3]. Preeclampsia is a complex multi-system disease, diagnosed by sudden onset hypertension (>20 weeks gestation) and at least one other associated complication including proteinuria, other maternal organ dysfunction or fetal growth restriction [4].

Poor implantation and placentation in the first trimester of pregnancy are widely accepted to be the sentinel causes of pregnancy diseases including preeclampsia. Inadequate extravillous trophoblast invasion and impaired spiral artery remodeling results in reduced uterine blood flow leading to placental ischemia [1]. The damaged placenta releases toxins into maternal blood causing systemic inflammation and widespread maternal endothelial dysfunction, resulting in the maternal syndrome of preeclampsia [1], [5].

Galectins are animal (soluble) lectins abundantly expressed at the maternal-fetal interface [6]. Dysregulated expression of galectins-1,2,3,7,9, 13 and 14 is associated with preeclampsia [6], [7], [8], [9], [10], [11]. Galectin-7, expressed by first-trimester syncytiotrophoblast and extravillous trophoblast [12], [13], is abnormally elevated in chorionic villous samples [14] and first-trimester serum [12] from women who subsequently develop pre-term preeclampsia. In vivo administration of galectin-7 causes preeclampsia-like features including hypertension, albuminuria and impaired placentation in pregnant mice [14]. Non-pregnant mice treated with gal-7 do not develop hypertension or albuminuria, demonstrating that galectin-7 acts via the placenta to cause preeclampsia-like features in this model [14].

We previously showed that in mice, exogenous galectin-7 induces alterations to tissue renin-angiotensin-(aldosterone)-system (RAS) homeostasis and drives a pro-inflammatory placental state [14]. In a healthy pregnancy, activation of the maternal renal RAS and circulating renin-angiotensin-aldosterone system (RAAS) expands the maternal cardiovascular system, maintaining blood pressure and increasing renal blood flow [15]. In preeclampsia, alterations to the circulating RAAS and placental RAS are clear [15], [16]: prorenin, angiotensinogen (AGT), ACE (angiotensin converting enzyme), and the AT1R (angiotensin II type 1 receptor) are all upregulated in the placenta [17], [18], [19]. Placental oxidative stress is another key driver of preeclampsia. Reactive oxygen species (ROS) have critical roles in the development of vascular disease via their involvement in endothelial dysfunction [20]. Although during uncomplicated pregnancies there is an increase in ROS production, in preeclampsia a further elevation in ROS is found in the placenta and maternal circulation causing cytokine and anti-angiogenic factor release into the maternal circulation which leads to endothelial dysfunction, a key feature in the pathophysiology of [21]. One tissue source of ROS, are the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases which play a central role as ‘kindling radicals’ that affect other enzymes [20]. Angiotensin II (AngII) drives ROS production via NADPH oxidases in many tissues [22]. Galectin-7 treatment causes ROS accumulation in bladder cancer cell lines [23], but the mechanism leading to this accumulation remains unknown.

In this study we aimed to investigate the mechanism by which galectin-7 induces alterations to the tissue RAS homeostasis and ROS production using both human and mouse models. We hypothesized that galectin-7 induces alterations in the production of either placental RAS or NADPH oxidases (or both) to drive the dysregulated RAS and ROS production seen in preeclampsia.

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