The Functional Role of the Renin–Angiotensin System in Pregnancy and Preeclampsia

doi:10.1016/j.placenta.2008.06.011

Placenta

Volume 29, Issue 9, September 2008, Pages 763-771

https://doi.org/10.1016/j.placenta.2008.06.011 Get rights and content

Abstract

During normal pregnancy, the renin–angiotensin system (RAS) plays a vitally important role in salt balance and subsequent well-being of mother and fetus. In this balance, one must consider not only the classical renal RAS but also that of the uteroplacental unit, where both maternal and fetal tissues contribute to the signaling cascade. Many studies have shown that in normal pregnancy there is an increase in almost all of the components of the RAS. In derangements of pregnancy this delicate equilibrium can become unbalanced. Preeclampsia is one such case. It is a disorder of pregnancy characterized by hypertension, proteinuria and placental abnormalities associated with shallow trophoblast invasion and impaired spiral artery remodeling. Despite being a leading cause of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Immunological mechanisms and the RAS have been long considered to be involved in the development of preeclampsia. Numerous recent studies demonstrate the presence of the angiotensin II type I receptor agonistic autoantibody (AT₁-AA). This autoantibody can induce many key features of the disorder and upregulate molecules involved in the pathogenesis of preeclampsia. Here we review the functional role of the RAS during pregnancy and the impact of AT₁-AA on preeclampsia.

Section snippets

Introduction of the classical RAS pathway

The circulating renin–angiotensin system, herein RAS, is a signaling cascade that plays a key role in regulating blood pressure and electrolyte balance. It is classically described in the kidney. The enzyme renin is synthesized and released by juxtaglomerular cells of the afferent renal arterioles in response to low blood pressure and low circulating sodium chloride. Renin release is mediated in part by prostaglandins produced by cells of the kidney's macula densa [1]. Renin enzymatically

A local RAS is present in the placenta

In addition to the classical view of the RAS there is accumulating evidence indicating components of the renin–angiotensin system are synthesized in many tissues, such as the brain, heart, ovary, and placenta [8], [9].

One of the major extra-renal RAS during pregnancy is in the placenta. As early as 1967, Hodari et al. described a placental RAS and identified a renin-like substance in human placental tissue [10]. Renin expression in cultured chorionic cells was first reported by Symonds in 1968

Regulation of the RAS during pregnancy

In humans, the RAS undergoes major changes in response to pregnancy. There is an early increase in renin due to extra-renal local release by the ovaries and maternal decidua [16]. Angiotensinogen synthesis by the liver is increased by circulating estrogen produced by the growing placenta. This leads to increased serum ANG II and aldosterone levels [17]. ACE is the only RAS component that decreases during pregnancy [18]. Table 1 compares the levels of serum RAS components between non-pregnant

Preeclampsia is characterized by significant alterations in the RAS

Preeclampsia is a pregnancy-specific syndrome of hypertension and proteinuria resulting in substantial maternal and neonatal morbidity and mortality. The condition is also characterized by placental abnormalities, such as decreased invasion by extravillous trophoblasts into maternal spiral artery endothelium. In advanced stages the clinical symptoms may include cerebral edema, renal failure and the HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome. The clinical management of

Role of AT₁-AA in placental abnormalities

Placentas of preeclamptic women are often small, exhibit shallow trophoblast invasion, aberrant spiral artery remodeling and reduced uteroplacental blood flow. The triggering factor and mechanism of these changes have not been determined. There is a growing body of evidence indicating that AT₁-AA and its derangement of the RAS could influence these transformations and contribute to the pathogenesis of preeclampsia.

Key animal models used to study the RAS and hypertensive disorders of pregnancy

It has become clear that preeclampsia is a vascular disease involving the interaction of multiple cell types, including trophoblasts, endothelial cells, vascular smooth muscle cells and others. To fully understand the interplay among these cells in response to alterations in the RAS it will be necessary to decipher the intercellular signaling pathways involved. This is a major reason why animal models, in which complex cellular interactions can be studied, will play an especially important role

Key animal models involving the AT₁-AA and preeclampsia

The above experiments did not highlight the role of AT₁-AA in the development of hypertension in pregnancy. To address this issue, Dechend et al. mated female transgenic rats expressing the human angiotensinogen gene with male rats expressing the human renin gene [89]. Much like the mice of Takimoto et al., these rat dams demonstrated hypertension and proteinuria late in pregnancy that resolved upon delivery. They also developed fibrin deposition in their glomeruli and their placentas

Conclusions and significance

The renin–angiotensin system has long been thought to play an important role in placentation, normal pregnancy and the pathophysiology of preeclampsia. How all the components of the system interact during normal and abnormal pregnancy has yet to be entirely understood. While there is a general upregulation of the RAS in normal pregnancy, this delicate balance is lost preeclampsia.

The central role of the placenta in preeclampsia is undisputed. Specific factors, such as sFlt-1, liberated by the

Acknowledgements

We would like to thank Dr Rodney Kellems for many informative discussions and his constructive comments, as well Dr Susan Ramin for her support and clinical insight.

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Published by Elsevier Ltd.

The Functional Role of the Renin–Angiotensin System in Pregnancy and Preeclampsia

Abstract

Section snippets

Introduction of the classical RAS pathway

A local RAS is present in the placenta

Regulation of the RAS during pregnancy

Preeclampsia is characterized by significant alterations in the RAS

Role of AT1-AA in placental abnormalities

Key animal models used to study the RAS and hypertensive disorders of pregnancy

Key animal models involving the AT1-AA and preeclampsia

Conclusions and significance

Acknowledgements

Kidney Int

Placenta

J Biol Chem

Genomics

Front Neuroendocrinol

Am J Obstet Gynecol

Kidney Int

Semin Nephrol

Eur J Obstet Gynecol Reprod Biol

Biochem Biophys Res Commun

Kidney Int

Biochem Biophys Res Commun

Am J Pathol

Placenta

Am J Hypertens

J Biol Chem

Reprod Biomed Online

Am J Obstet Gynecol

Trends Cardiovasc Med

Kidney Int

Am J Kidney Dis

Kidney Int

Am J Obstet Gynecol

Int J Gynaecol Obstet

Am J Obstet Gynecol

Am J Hypertens

Placenta

Trends Mol Med

Autoimmun Rev

Placenta

Semin Fetal Neonatal Med

Mol Aspects Med

Prostaglandins stimulate renin secretion and renin mRNA in mouse renal juxtaglomerular cells

Am J Physiol

Expression of the subtype 2 angiotensin (AT2) receptor protein in rat kidney

Hypertension

Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage

Am J Physiol Heart Circ Physiol

The uteroplacental renin-angiotensin system: a review

Exp Clin Endocrinol

A renin-like substance in the human placenta

Obstet Gynecol

Production of renin by in vitro cultures of human chorion and uterine muscle

Nature

Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants

J Clin Invest

Human decidua is a major source of renin

J Clin Invest

Definitive molecular evidence of renin-angiotensin system in human uterine decidual cells

Hypertension

Human spiral artery renin-angiotensin system

Hypertension

Changes in active and inactive renin throughout pregnancy

J Clin Endocrinol Metab

Angiotensin-(1–7) in normal and preeclamptic pregnancy

Endocrine

Regional flow-pressure relationship in response to angiotensin in the intact dog and sheep

Circ Res

Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness

Nat Med

AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase

Circulation

Angiotensin II decreases system A amino acid transporter activity in human placental villous fragments through AT1 receptor activation

Am J Physiol Endocrinol Metab

Hypertension induced in pregnant mice by placental renin and maternal angiotensinogen

Science

Pregnancy-induced changes in renin gene expression in mice

Biol Reprod

Role of AT₁-AA in placental abnormalities

Key animal models involving the AT₁-AA and preeclampsia