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.
Highlights
Hypertensive diseases of pregnancy are the leading cause of maternal mortality in Latin America and the Caribbean and the second major cause of maternal mortality in developed countries
We describe the contributions of these various renin-angiotensin system (RAS) to the clinical syndrome of preeclampsia and help to explain why other conditions like chronic hypertension, renal disease, diabetes mellitus and some single nucleotide polymorphisms (SNPs) of angiotensinogen (AGT) are risk factors for preeclampsia [11]
We suggest that increased production of placental prorenin and Ang peptides and recruitment of Ang II type 1 receptor subtype (AT1R)-AAs, stimulate the intrarenal renin-angiotensin systems (iRAS) while continuing to suppress the maternally derived JGAregulated circulating renin-angiotensin-aldosterone system (RAAS)
Summary
Hypertensive diseases of pregnancy are the leading cause of maternal mortality in Latin America and the Caribbean and the second major cause of maternal mortality in developed countries. One of the most severe forms of hypertension in pregnancy is preeclampsia, which can lead to eclampsia and commonly results in maternal and fetal death [1, 2]. The placenta is quite rightly regarded as the cause of preeclampsia, as removal of the placenta is the only effective treatment. There has been a long-standing search for placental causes of preeclampsia
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