Causes and Consequences of the Dysregulated Maternal Renin-Angiotensin System in Preeclampsia

Abstract

A healthy pregnancy outcome depends on the activation of the renin-angiotensin-aldosterone system (RAAS) as a regulated, integrated response to the growing demands of the conceptus. Both the circulating RAAS and the intrarenal renin-angiotensin system (iRAS) play major roles in cardiovascular function and fluid and electrolyte homeostasis. The circulating RAAS becomes dysfunctional in preeclampsia and we propose that dysregulation of the iRAS plays a role in development of the clinical syndrome known as preeclampsia. Experimental studies in animals have shown that placental renin, when released into the maternal circulation, can cause hypertension. We postulate that abnormal placental development is associated with over-secretion of renin and other RAS proteins/angiotensin (Ang) peptides by the placenta/decidua into the maternal circulation. We hypothesise that this is because of increased shedding of exosomes and other placental particles into the maternal circulation that not only contain RAS proteins and peptides but also microRNAs (miRNAs) that target RAS mRNAs, and Ang II type 1 receptor autoantibodies (AT₁R-AAs), that are agonists for, and have the same actions as, Ang II. As a result, there is both suppression of the circulating RAAS that is responsible for maintaining maternal homeostasis and activation of the iRAS. Together with altered vascular reactivity to Ang peptides, the iRAS causes hypertension, renal damage and secondary changes in the neurohumoral control of the maternal circulation and fluid and electrolyte balance, which contribute to the pathophysiology of preeclampsia.

Keywords: angiotensin receptor autoantibodies; intrarenal angiotensin; miRNAs; preeclampsia; renin-angiotensin system; utero-placental.

Figure 1

The postulated system via which placental/decidual renin-angiotensin system (RAS) proteins and peptides, miRNAs that target renin and auto-antibodies to the Angiotensin II type I receptor (AT₁R-AA) interact with the juxtaglomerular (JGA) to control circulating active renin levels and the intratubular RAS. Red arrows denote where pathway is inhibitory. Green arrows are stimulatory.

Figure 2

Components of the renin-angiotensin system (RAS) responsible for the activity of circulating and tissue RASs in pregnancy. Renin, or prorenin binding to the prorenin receptor ((P)RR), can cleave angiotensin I (Ang I) from Angiotensinogen (AGT). Ang I is converted to Ang II by a dipeptidyl carboxypeptidase, angiotensin converting enzyme (ACE). Ang II can act on either an Ang II type 1 receptor subtype (AT₁R) or a type II receptor subtype (AT₂R). The interaction of Ang II with its AT₂R opposes the vasoconstrictor actions of Ang II mediated via its AT₁R. Ang II can be converted by aminopeptidase A (APA) to Ang III which is converted to Ang IV. Ang IV acts on insulin regulated aminopeptidase (IRAP). Ang II is converted by the monopeptidyl carboxypeptidase ACE2 to Ang-(1–7), which acts on its own G-protein coupled receptor (MasR), and has actions similar to those of Ang II mediated via the AT₂R. Ang peptides can often interact with different Ang receptors [see also (31)].

Figure 3

Actions of the angiotensin peptides on the cardiovascular system and on fluid and electrolyte homeostasis in normal pregnancy.

Figure 4

Description of how oxidative stress in the placenta caused by shallow placentation or reduction in uterine perfusion pressure could cause dysregulation not only of the placental RAS but also the maternal and intrarenal RASs. Upper panel: Normal control of the placental RAS in early and mid-late gestation. We have identified O₂ regulated placental microRNAs (miRNAs) that target key RAS mRNAs. As well, expression of the placental RAS is regulated by hormones such as hCG, cAMP (19) and the combination of the steroid hormones oestrogen (E₂) and progesterone [P; (20)]. In early gestation there is minimal shedding of placental particles and molecules (yellow triangle) and the total placental mass is very small but RAS targeting miRNAs that are oxygen-regulated are suppressed so even though the placental RAS is upregulated by low O₂ no RAS proteins/peptides or O₂ regulated miRNAs (17) are released. At 12 weeks, maternal blood flow increases and pO₂ rises so that O₂ regulated miRNAs are upregulated, leading to reduced placental RAS activity. Thus, despite the gestational increase in exosomal shedding (21), escape of placental RAS proteins and peptides into the maternal circulation is curtailed. Lower panel: The preeclamptic placenta. In preeclampsia there is placental ischaemia/reperfusion resulting from shallow placentation or a reduction in uterine perfusion pressure (6, 22, 23). Fluctuations in placental _pO₂ lead to dysregulation of O₂ sensitive miRNAs and activation of the placental RAS. Together with excess placental shedding there is increased release into the maternal circulation of RAS proteins and peptides and of miRNAs that target the maternal RAS. These secretions are not regulated by homeostatic demand, creating a situation analogous to 2-Kidney 1-Clip hypertension or Ang II dependent hypertension; Ang II infusions have been used to model preeclampsia (8). There is also an added contribution of placental miRNAs known to target the RAS (24) that cause renin independent hypertension (25). Autoantibodies that acts as agonists to the AT₁R (AT₁R-AA) released from the decidua (4) have the same actions as Ang II. MiRNAs that target the maternal RAS and AT₁R-AAs also suppress JGA-mediated renal renin release. Thus, there is a greater release of decidual/placental renin and Ang peptides into the maternal circulation, which lacks neurohumoral control so that the circulating system is not in accordance with homeostatic demand.

Figure 5

Mechanisms via which excess release of molecules from decidual/placental tissues that target the maternal kidney and cardiovascular system could cause hypertension and renal damage. Blue arrows represent suppression of maternal systems and receptors, red arrows represent stimulation of maternal systems and receptors. Dashed boxes highlight those pathways that have not been validated experimentally.