the role of the renin–angiotensin–aldosterone system in preeclampsia genetic polymorphisms and...

7/25/2019 The role of the reninangiotensinaldosterone system in preeclampsia genetic polymorphisms and microRNA.pdf

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The role of the reninangiotensin

aldosterone system in preeclampsia:

genetic polymorphisms andmicroRNA

Jie Yang1, Jianyu Shang1, Suli Zhang1, Hao Li1 andHuirong Liu1,2

1Department of Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 Xitoutiao, You An

Men, Beijing 100069, Peoples Republic of China 2Department of Physiology, Shanxi Medical University, Taiyuan,

Shanxi 030001, Peoples Republic of China

Correspondence

should be addressed to H Liu

Email

[email protected]

Abstract

The compensatory alterations in the renninangiotensinaldosterone system (RAAS)

contribute to the saltwater balance and sufficient placental perfusion for the subsequent

well-being of the mother and fetus during normal pregnancy and is characterized by an

increase in almost all the components of RAAS. Preeclampsia, however, breaks homeostasis

and leads to a disturbance of this delicate equilibrium in RAAS both for circulation and the

uteroplacental unit. Despite being a major cause for maternal and neonatal morbidity and

mortality, the pathogenesis of preeclampsia remains elusive, where RAAS has been long

considered to be involved. Epidemiological studies have indicated that preeclampsia is a

multifactorial disease with a strong familial predisposition regardless of variations in ethnic,

socioeconomic, and geographic features. The heritable allelic variations, especially the

genetic polymorphisms in RAAS, could be the foundation for the genetics of preeclampsia

and hence are related to the development of preeclampsia. Furthermore, at a

posttranscriptional level, miRNA can interact with the targeted site within the 3 0-UTR of the

RAAS gene and thereby might participate in the regulation of RAAS and the pathology of

preeclampsia. In this review, we discuss the recent achievements of genetic polymorphisms,

as well as the interactions between maternal and fetal genotypes, and miRNA

posttranscriptional regulation associated with RAAS in preeclampsia. The results are

controversial but utterly inspiring and attractive in terms of potential prognostic

significance. Although many studies suggest positive associations with genetic mutations

and increased risk for preeclampsia, more meticulously designed large-scale investigations

are needed to avoid the interference from different variations.

Key Words

" Pre-eclampsia

" Reninangiotensin system

" Polymorphism

" Genetic

" microRNA

Journal of Molecular

Endocrinology

(2013) 50, R53R66

Introduction

Preeclampsia,characterized ashypertension(O140/90 mmHg)

after 20 weeks gestation accompanied by proteinuria

(O300 mg/l), represents a major cause of maternal and

neonatal morbidity and mortality, leading to devastating

effects to mothers and their children. According to recent

epidemiological studies, 57% of pregnant women in the

world have suffered from this disease (Kuc et al. 2011).

Various as the theories for pathogenesis of preeclampsia

JournalofMolecularEndocrinology

Review J YANGand others Role of RAAS in preeclampsia 50:2 R53R66

http://jme.endocrinology-journals.org 2013 Society for Endocrinology

DOI: 10.1530/JME-12-0216 Printed in Great BritainPublished by Bioscientifica Ltd.
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are, the exact underlying molecular mechanisms remain

unclear but are likely to be multifactorial: endothelial

cell dysfunction, excessive vasoconstriction (Roberts &

Gammill 2005), inflammation, immunological disorder

(Hubel et al. 2007), etc. Of the multifactorial impact

factors, the reninangiotensinaldosterone system (RAAS)

serves as the major cause for shallow trophoblast invasion

and impaired spiral artery remodeling, which are the most

paramount and fundamental pathological alterations

followed by a series of complications. The compensatory

and delicate changes of RAAS during normal pregnancy

are hard to counterbalance for preeclamptic women,

resulting in body capillary constriction, renal damages,

disorders of salt and water balance, etc. However, the

etiology of this dysfunction requires further explorations.

There exists both a classical RAAS and a local

reninangiotensin system during pregnancy

The RAAS contributes to blood pressure regulation

and body fluid through a series of enzymatic reactions

induced by its primary components: renin, angio-

tensinogen (AGT), angiotensin-converting enzyme

(ACE), angiotensin I (ANG I), angiotensin II (ANG II),

angiotensin a receptor type I (AT1R), and angiotensin

receptor type 2 (AT2R). In response to low blood pressure

and low circulating sodium chloride, renin, synthesized

and secreted by juxtaglomerular cells of the afferent renal

arterioles, catalyzes the cleavage of AGT made in the liver

to ANG I. This is the rate-limiting step of the reninangiotensin system (RAS) cascade. Then, this ten amino

acid peptide, without any biological function as we

presently know, is cleaved by ACE, which is made

primarily in lung endothelium, into ANG II, a biologically

active eight amino acid molecule. ACE2, a homolog of

ACE, is a new component of RAS and can cleave a single

residue from ANG II to form angiotensin (17) (ANG

(17)), or from ANG I to angiotensin (19) (ANG (19))

(Anton & Brosnihan 2008), whose functions include a

vasodilator response and antidiuresis in water-loaded

animals. Therefore, ACE2, ANG (17), and ANG (19) are

regarded to modulate the effects of RAS on vascular tone,neutralizing excessive contraction. There exist two major

types of angiotensin receptors: AT1R and AT2R, both of

which belong to seven transmembrane G-protein-coupled

receptor families, though their distributions and functions

are totally different. Via activation of AT1R or AT2R,

ANG II is regarded as a well-known versatile effector

involved in vasoconstriction, sympathetic activity, cell

viability, and the release of different molecules, such as

aldosterone (ALD). Through a major activation of AT1R

and then the primary aldosterone-synthesizing enzyme

(CYP11B2), in the zona glomerulosa of the adrenal cortex,

ANG II affects the production of ALD synthesis, which

plays a critical role in the regulation of salt and water

retention and excretion to maintain sufficient blood fluids

and electrolyte balance.

It has been confirmed that the components of RAS are

not unique to the kidney but are synthesized in many

tissues, among which one of the major local RAS during

pregnancy is in the uteroplacental unit (placenta also

named fetal origin and decidua named maternal origin)

(Shah 2006). Since the first-time pro-renin, AGT, ACE,

ANG II and ANG I, AT1R were identified in fetal placental

tissues (Liet al. 1998), the expression of renin, AGT, ACE,

and AT1R has been observed in the first trimester human

deciduas (Shaw et al. 1989), and more recent studies via

human third trimester decidual cells also have demon-strated the presence of AGT and renin (Li et al. 2000).

Other studies of the decidual spiral arteries have indicated

the expression of AGT, renin, ACE, and AT1R (Morgan

et al. 1998a,b). Moreover, it has been demonstrated that

immunocytochemical expression of ANG (17) and ACE2

was widely distributed throughout the human fetal

placental unit during gestation (Valdeset al. 2006,Neves

et al. 2007). Therefore, all the necessary components of

RAS have been found both in maternal decidua and in

the fetal placental tissues.

Compensatory regulation of RAAS during

pregnancy

During normal pregnancy, both body fluid and the RAAS

undergo major changes. There is a marked enlargement of

plasma volume that starts in the first trimester, accelerates

in mid-gestation, and stabilizes after around the 34th week

of gestation (Piraniet al. 1973). In other words, this new

steady state in pregnancy reflects a downward resetting of

the osmolarity thresholds for thirst sensation and vaso-

pressin release, which finally leads to an increase in salt

and water strengthening placental perfusion to protect

the pregnant woman and her fetus (Escher & Mohaupt

2007). As the most principal part in the renal control of

body fluid, nearly all the components of RAAS experience

an increase except ACE, the only component decreasing

or leveling off at the nonpregnant concentration (Merrill

et al. 2002). An early increase in renin is observed due to

the local release by maternal decidua and ovaries (Hsueh

et al. 1982), and the growth of circulating estrogen

generated by fetus placenta promotes the AGT synthesis


Review J YANGand others Role of RAAS in preeclampsia 50:2 R54




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in the liver, which leads to obvious rises in serum ANG II

(Brown et al. 1988). ALD level shows an upward trend

mainly corresponding to the requirement for volume

expansion. Meanwhile, in both plasma and urinary levels,

there is also an increase both in ANG (17) and ACE2

(Valdes et al. 2001, Oudit et al. 2003, Turner 2003).

Furthermore, in rat pregnant models, a study conducted

by Levy et al. (2008) indicated that the uterus and

placentas contributed to Ace2 expression and activity

during preeclampsia. The placenta was the foremost total

contributor, although the kidney was responsible for the

highest levels of ACE2 activity. They found that during

pregnancy, ACE abundance in reproductive organs during

the third trimester of pregnancy was commensurate with

a systemic vasodilatory state both in normotensive and in

hypertensive rats. ACE activity in the uterus was affected

by salt-loading. These studies demonstrate the importance

of transient overexpression of ACE2 and its elevatedactivity in modulating systemic and local hemodynamics

in the uteroplacental unit during pregnancy. However,

we know little about the underlying exact mechanisms.

Although ANG II levels increase during pregnancy,

normotensive pregnant women are less responsive to its

vasopressor effects, which was substantiated by the

historic study conducted by Assali & Westersten (1961)

showing that the required ANG II concentration of a

pregnant woman is twice that needed in a nonpregnant

woman to achieve the same vasomotor response. This

reduced ANG II sensitivity is considered to be due to the

increased progesterone and prostacyclins (Gant et al.1980), as well as a little inactivation of AT1R by reactive

oxygen species (ROS;Abdallaet al. 2001).

Changes in both circulating RAAS and local

RAS during preeclampsia

Women with preeclampsia suffer from an utterly different

RAAS state (Table 1) and develop a much poorer control of

sodium loading and a substantial fluctuation of sodium

level in sera with avid retention of sodium and slow

excretion of additional sodium loads, when compared

with normotensive pregnant women who have much

better tolerances of sodium intake and slight changes in

either weight or plasma volume (Symonds et al. 1975,

Herseet al. 2007). This implies that there is a dysfunction

of saltwater balance that is dominated mainly by ALD.

Moreover, compared with the increase in RAAS com-

ponents in normotensive pregnancy, the circulating levels

of renin, ANG I, ANG II, ANG (17), and ALD are much

lower, yet with little fluctuation of ACE levels (Granger

et al. 2001, Merrill et al. 2002); stranger still, there is a

relatively higher level of ALD for the given level of renin

(Gallery & Brown 1987) and worse, pregnant women are

highly sensitive to the pressor effects of ANG II partly due

to heterodimerization of AT1R (Quitterer et al. 2004,

Abdallaet al. 2005). As for local uteroplacental RAS, there

are some various and controversial results: recently,

Herse et al. (2007) argued that excessive expression of

the AT1R receptor in maternal deciduas is the only change

observed in local RAS, without any increase in renin

production in decidua of preeclamptic patients. By

contrast, Shah et al. (2000) demonstrated an increase in

renin level in the deciduas vera of preeclamptic women.

A recent clinical trial performed by Anton et al. (2008)

suggested that in the chorionic villi of preeclampsia

patients, an essential part of the placenta responsible for

regulating nutrient and oxygen exchange between themother and the fetus, ANG II levels and AT1RmRNA were

significantly higher despite a decrease in circulating

ANG II when compared with normal pregnancies.

Furthermore, in murine models of antenatal maternal

hypoxia responsible for the development of preeclampsia,

such stress elevated the expression of AGT and ACE by

post-transcriptional mechanisms in murine placenta

(Goyal e t a l. 2011). Another symptom leading to

Table 1 Serum RAAS levels in normotensive and preeclamptic

pregnancies vs nonpregnancies. Pregnancy is characterized by

marked alterations of RAAS. In pregnancy, the increase in

almost all RAAS components leads to a marked enlargement of

plasma volume for sufficient placental perfusion. On the other

hand, in preeclampsia, the gravid experiences hypertension

accompanied by damaged control of saltwater balance mainly

because of elevated AT1R activity and sensitivity neutralizing

decreased ANG II concentration

RAAS componets

Normotensive

pregnancy

Preeclamptic

pregnancy

AGT CC KRenin CC CRenin activity CC Z/KALD CC KANG II CC Z/KANG II activity K CCANG (17) CC K

ACE K Z/KACE2 CC KACE2 activity CC KAT1R Z CC

CC, significantly increased over nonpregnancy; C, slightly increased overnonpregnancy; Z, same as nonpregnant; K, decreased compared withnonpregnancy.






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preeclampsia is pregnancy-induced hypertension, of

which the rat model suggested that ANG (17) concen-

trations decreased both in the uterus and placenta, so did

Ace2mRNA levels (Neveset al. 2008). The possible reasons

for this divergence involve the different sample sizes,

chosen tissues, and defining criteria for preeclampsia,

which suggests that it is necessary to conduct further

investigation. In summary, preeclampsia is characterized

by a series of significant alterations in RAAS worthy of

deeper research (Fig. 1).

Genetic mutations in preeclampsia play

a big role

Right now, we still know little about the exact reasons

for the dysfunction of RAAS in preeclampsia, although

several pathophysiological mechanisms have been pro-

posed including endothelial damage, oxidative stress, andautoimmunity. Yet inspiringly, from an epidemiological

point of view, various genetic and environmental factors

have been considered to contribute to the pathogenesis

of preeclampsia due to a strong familial predisposition

observed in different geographic, socioeconomic, and

racial features (Hocher et al. 2008). Researchers, for

instance, reported that compared with the offspring or

relatives of normotensive pregnancies, daughters of

preeclamptic mothers suffered from much higher inci-

dence of risk for the disease ranging from 20 to 40%, 11 to

37% for sisters of preeclamptic women, and 22 to 47% in

twin studies (Mogrenet al. 1999,Esplinet al. 2001,Hocher

et al. 2008). Studies also showed paternal contributors

to the disease:Esplin et al. (2001)suggested an increased

risk of fathering a preeclamptic pregnancy among

males whose mothers once had preeclampsia, as shown

among males who previously fathered a preeclamptic

pregnancy with another partner (Lie et al. 1998). Trying

to separate the effect of maternal and fetal genetic factors

from environmental factors, Cnattingius et al. (2004)

suggested that via population-based Swedish Birth and

Multi-Generation Registries, genetic factors accountedfor more than 50% of the liability to preeclampsia,

maternal genes may contribute more than fetal genes

and genetic interaction effects between spouses. Naturally,

ever-increasing studies have been focusing on the role

of genes as candidates for this disorder. The genetic

polymorphisms involve various functional systems and

each of them requires a detailed review. Considering

the importance of RAAS in preeclampsia, this review

will be limited to the current views on genetic mutations

in RAAS.

Genetic polymorphisms associated with

decreased ALD level

Deficiency of ALD, a paramount hormone regulating

body fluid, has been considered to be involved in the

development of reduced placental perfusion and hyper-

tension leading to a variety of factors that cause

widespread dysfunction of the maternal vasculature

(Roberts et al. 2003, Sibai et al. 2005). The hypothesis

favored by current researchers is that a gestational increase

in plasma volume, regarded as a compensatory adaptation

to support placental perfusion and fetal substrate delivery,

is jeopardized in preeclampsia due to a decrease in ALD,

resulting in fluid deficiency and subsequent placental

ischemia (Gallery & Brown 1987,Roberts & Cooper 2001,

Takeda et al. 2002). Therefore, the reduced circulating

volume circumscribes placental blood supply, finally

inducing an elevated blood pressure during preeclampsia.

Compared with normal pregnancies, preeclamptic women

are proven to experience much lower levels of circulating

ALD (Shojaatiet al. 2004).

ANG (19)

ANG (17)

Vasodilation

Uteroplacentalperfusion

Adjustment ofsaltwater balance

Aldosterone

AT1 R

ANG ll

ANG l

AGT

ACE2

ACE2

ACE

Renin

Sensitivity

Vasocontraction

ANG (17)-RMas

Intrauterine growth retardation

Figure 1

Despite a significant decrease in most components, elevated sensitivity

of AT1R and its increased amount seem to account for hypertension and

intrauterine growth retardation in preeclampsia. The red arrows indicate

an increase in concentration while the blue arrows indicate a decrease in

concentration.






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CYP11B2 activity is impaired in preeclampsia partly

because of genetic polymorphisms. CYP11B2, a multi-

enzyme complex sharing 93% homology to CYP11B1,

comprised three enzymatic reactions conducting the

last but most important in ALD synthesis, whose activities

can be quantified separately through the determinationof urinary steroids. Compared with the increased tetra-

hydroaldosterone (TH-Aldo) during normal pregnancy,

a metabolite of urinary ALD, preeclampsia is charac-

terized by a higher level of TH-Aldos immediate precursor

18-OH-tetrahydrocorticosterone (18-OH-THA) cortico-

sterone -and lower levels of TH-Aldo, suggesting com-

prised ALD synthase (Fig. 2; Shackleton 1993, Shojaati

et al. 2004). To characterize the jeopardized CYP11B2

(Shojaatiet al. 2004), Shojaatiet al. demonstrated that the

reduced ALD synthesis was due to diminished methyl

oxidase activity with which genetic polymorphisms

appeared to be associated. Based on the altered urinary

steroid profile, they found two of five exon mutations

associated with an increased risk of preeclampsia R173K

and V386A-CYP11B2. R173KCYP11B2polymorphism was

slightly less frequent in preeclampsia, as it had been

reported previously (Portrat-Doyen et al. 1998), whereas

other studies claimed that it was related to low renin

hypertension in Chilean residents (Fardella et al. 1996).

The other was V386A-CYP11B2 polymorphism that had

been reported, compared with 4% in normotensive

pregnancies, to show up in 18% of patients with essential

hypertension closely related to preeclampsia (Pascoe

et al. 1992), although it solely appeared in preeclamptic

women in Kushiars own study.

Recently, the K344C/T CYP11B2 polymorphism

disrupting a putative steroidogenic factor-1 site (SF-1) in

CYP11B2 has attracted more attention and has been

reported as a loss-of-function mutation associated with a

high risk of preeclampsia, compared with the gain-

of-function in high ALD-to-renin ratio alleles in normal

pregnancies (Bauknecht et al. 1982, Lindheimer & Katz

1992,Wacker et al. 1995). The T-allele polymorphism in

the 5 0-flanking region of the CYP11B2 gene has been

reported to be more relevant in hypertensives than in

normotensives and has also been related to increasedALD levels (Davieset al. 1999,Tamakiet al. 1999,Komiya

et al. 2000, Poch et al. 2001, Nicod et al. 2003, Escher

et al. 2009). Nicod et al. (2003) were the first to posi-

tively associate the K344/CT CYP11B2 polymorphism

with increased ALD in selected hypertensive patients.

Recently, a study performed by Escher et al. (2009)

confirmed the hypothesis of the correlation of higher

ALD availability in normal pregnancies with lower

maternal blood pressure, and heterozygosity for SF-1

preferably in preeclampsia corresponded to hypertension

and deficiency in placental infusion. In other words, the

prevalence of gain-of-function homozygosity for SF-1prevented pregnancies from developing preeclampsia.

Interestingly, many studies have reported the low

expression of high ALD-to-renin ratio variants in pre-

eclampsia in the healthy, normotensive, nonpregnant

subjects, which strongly corroborates with the notion that

K344C/TCYP11B2polymorphism variants, instead of SF-

1-344T/T CYP11B2 genotype, predisposed women to

preeclampsia, as well as facilitating any additional

contributing factors to the increased risk of developing

preeclampsia (Lim et al. 2002, Nicod et al. 2003, Escher

et al. 2009). As reported in a research study conducted by

Procopciue et al. (2010), women with CC344 CYP11B2tended to experience an increased risk of preeclampsia

(3.21 vs 1.29 of those with CT344 CYP11B2), of which the

tendency appeared in mild preeclampsia and severe

preeclampsia, 1.49 and 2.01 with a significant statistical

difference respectively. They also found the CC344

CYP11B2 polymorphism was related to curtailed delivery

gestation and decreased birth weight of babies. Interest-

ingly, still, for a woman positive for M235T AGT or I/D

Urinary steroid metabolitesdetermined

DOC, THDOC

THB, THA

18,OH-THA

TH-AldoAldosterone

18-Oxydase

18-Hydroxycorticosterone

18-Hydroxylase

Corticosterone

11-Deoxycorticosterone

Pregnenotone

Cholesterol

CYP11A1/StAR

HSD3B2

CYP21A2

11-Hydroxylase (CYP11B1)

Peogesterone

CYP11B2

Figure 2

Adrenocortical steroidogenic pathway for ALD biosynthesis. StAR is

paramount for the rate-limiting step of movement of cholesterol into themitochondria, where cholesterol is cleaved by CYP11A1 to pregnenolone.

Then the compound is catalyzed by HSD3B2, CYP21A2, and CYP11B2 into

ALD. Urinary steroid metabolites can be quantified to assess the enzyme

activities of CYP11B2 consisting of three different enzymatic reactions.

In preeclampsia, the decreased TH-Aldo level accompanied by elevated

18-OH-THA indicates impaired CYP11B2 activity, specifically 18-oxidase

activity. DOC, 11-deoxycorticosterone; THDOC, tetrahydro-11-deoxycortico-

sterone; THB, tetrahydrocorticosterone; THA, tetrahydro-11-dehydrocortico-

sterone; 18-OH-THA, 18-OH-tetrahydrocorticosterone; TH-Aldo,

tetrahydroaldosterone. The red arrows indicate an increase in concentration

while the blue arrows indicate a decrease i n concentration.






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ALD (see below), a much higher risk of preeclampsia was

observed if she had a C344T CYP11B2 polymorphism.

However, some studies indicated a lack of association

(Mulatero et al. 2000, Percin et al. 2006). A negative

relationship of K344C/T CYP11B2 with pregnancy-

induced hypertension closely related to preeclampsia

was supported by a recent casecontrol study among 100

women in 2011 (Remrez-Salazaret al. 2011). Despite the

reduced serum ALD levels in gestational hypertensive

women, neither was the genotype of K344T/C of

CYP11B2 related with gestational hypertension nor with

ALD levels at delivery. A direct comparison of these

polemical results is often limited by the missing infor-

mation on primiparity, the ethnic divergence between

different study groups, and the concern for any other

patient abnormalities, such as diabetes. Moreover, pre-

eclampsia is regarded as a multifactorial disease with

various factors contributing to the different extents, ofwhich genetic divergence is likely to play a large role.

Moreover, decreased ALD concentration might be

attributed to altered activity of the mineralocorticoid

receptor (MR), due to the binding of ALD and MR

conducting the major functions of ALD in renal sodium

reabsorption and potassium excretion. Despite the

increased competitive combinations of other hormones

against ALD in preeclampsia (Myles & Funder 1996), either

gaining or loss-of-function mutations of MR genes such

as the S810L mutation appeared to be associated with the

alteration of ALD in preeclampsia (Gelleret al. 1998,2000,

Pearce et al. 2003, Procopciue et al. 2010). However, theoverall assumption favored by most scientific research is

that the genetic polymorphisms of MR are rare and cannot

be a factor significant enough to articulate the frequency

of preeclampsia (Nicod et al. 2003, Escher et al. 2009),

although this assumption is supported by observations

in very small subsets of preeclamptic patients by other

groups (Schmider-Rosset al. 2004,Tempferet al. 2004).

ACEpolymorphism in preeclampsia

The ACE I/D polymorphism seems to be related to

hypertension.Rigatet al. (1990)made a striking discovery

after performing deeper studies of the ACE gene for the

detection of the well-known polymorphism involving the

presence (insertion, I) or absence (deletion, D) of a 287 bp

sequence of DNA in intron 16 of this gene, located on

the long arm of chromosome 17(17q23) with 26 exons

and 25 introns. More evidence corroborate that the

DD genotype is commensurate with higher ACE levels,

whereas the II genotype is associated with lower ACE levels

and the ID genotype with middle levels (Rigatet al. 1990,

1992). The reason for the higher ACE levels in the D allele

is partly due to the silencer sequence in the 1 allele (Choi

et al. 2004). Furthermore,Uedaet al. (1995)found that DD

carriers suffered from a more marked increase in venous

concentration of ANG II and blood pressure compared

with II carriers after injection of ANG I. In consideration

of the contribution of high ACE to hypertension (Wilson

et al. 1991, Nogueira et al. 2009), naturally, there is the

favored hypothesis of a functionalpolymorphism involved

in pathophysiological conditions of hypertension. Based

on clinical studies, some researchers failed to find a

significant association between the I/D polymorphism

and hypertension (Jeunemaitreet al. 1992,Schmidt et al.

1993,Agachan et al. 2003), whereas several other studies

reported a positive association between the D allele and

high blood pressure (Iwai et al. 1994, Schunkert etal. 1994,

Staessen et al. 1997, Giner et al. 2000). This is probablybecause it is necessary to perform sensitivity analyses in

subgroups based on gender, ethnicity, mean ages, and

genotyping methods. According to these data, there was a

substantial relationship between the D allele and hyperten-

sion in women and in Asians (Kim et al. 2004). Further-

more, with the help of transgenic mice models of these

three functional copies of theACEgene (DD, DI, II),Krege

et al. (1997) found that there was no marked difference

in blood pressure between DD type and II type, although

the higher activity of ACE in serum was easily detected in

the DD type. This discrepancy suggests the combination

ofACE gene expression and additional environmental orgenetic factors would greatly affect blood pressure.

The consequence of ACE in blood pressure by

regulating the generation of ANG II has stimulated ever

more investigations on the role of the ACE I/D poly-

morphism in the pathogenesis of preeclampsia. The

results are conflicting, presumably attributable to

differences in study population, ethnics, genetic basis,

and sample size. It has been assumed that lack of

association between the ACE I/D polymorphism appeared

more in Koreans (Kim et al. 2004), Colombians (Serrano

et al. 2006), Greeks, and Black South African women

(Boubaet al. 2003,Roberts et al. 2004,Akbar et al. 2009).Recently, in a meta-analysis using data from 17 studies

(Shaiket al. 2011), Shaiket al. argued that the presence of

the ACE I/D polymorphism was not related to increased

risk of preeclampsia. In southeastern Iran (Salimi et al.

2011), northern India (Aggarwalet al. 2011), and Turkey

(Morganet al. 1998a,b,Bereketoglu et al. 2012), however,

the presence of the D allele of the ACEgene was related to

increased risk of preeclampsia. Uma et al. (2010) found






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that the DD genotype of ACE was related to early-onset

preeclampsia, although no marked changes in RAS were

detected. A recent study byBereketoglu et al. (2012)also

suggested a higher incidence of the DD genotype in

Turkish preeclampsia patients in all the three models

codominant, recessive, and dominant. Meanwhile, based

on 30 casecontrol studies, a meta-analysis byChenet al.

(2012) showed a strong relationship between the DD

genotype of ACE and a higher risk of pregnancy

hypertensive disorders, especially for Asians and Cauca-

sians. Furthermore, Rahimi etal. (2013) confirmed that the

ACE D allele and DD genotype were more associated with

increased risk of mild preeclampsia (1.99- and 2.34-fold

respectively) than severe preeclampsia (1.61- and 1.56-fold

respectively), similar to the results of the study by Mando

et al. (2009). These results substantiated the theory that

severe and mild preeclampsia patients are characterized by

genetic heterogeneity (Oudejanset al. 2007). Furthermore,they demonstrated that the ID genotype of ACEis associated

with lower total antioxidant capacity levels compared

with the II genotype, which suggested the lipid per-

oxidation and oxidative stress, known to be involved in

the pathogenesis of preeclampsia, and this might be

influenced by polymorphisms in the genes. Moreover, a

recent study by Procopciuc et al. (2011) showed that a

preeclampticwoman withat least one mutated D-ACE allele

suffered from a higherfrequency of maternal complications,

a lower gestational age, and lower birth weight babies.

Although ever-increasing human studies are conducted to

prove a positive association between ACE I/D poly-morphism with preeclampsia, various sample size, genetic

basis, and ethnicity, a more appropriate mouse model or

other basic scientific research may offer more information.

Genetic polymorphisms in AT1R, AGT,

and renin

Other RAS gene polymorphisms, such as AT1R A1166C,

AGTMet235Thr, AGT Thr174Met, and 83A/G-REN, seem

related to preeclampsia. Similarly, studies are diverging

on the relationship ofAT1R A1166C and preeclampsia

some claiming a higher risk of pregnancy-induced

hypertension commensurate with the AT1R A1166C

polymorphism (Shanmugam et al. 1993, Hu et al. 2000,

Seremak-Mrozikiewiczet al. 2005,Procopciuc et al. 2011,

Salimiet al. 2011), yet others are failing to report marked

differences (Morgan etal. 1998a,b, Li etal. 2007) partly due

to the multifactorial character of preeclampsia. Moreover,

Salimi et al. recently demonstrated a lack of synergistic

effects between two alleles ofACE D and AT1RA116C on

the risk of preeclampsia. As for AGTpolymorphisms, the

exon 2 polymorphism M 235T has been extensively

explored (Kobashi et al. 1999, Suzuki et al. 1999). Ward

et al. (1993) observed a significant association of pre-

eclampsia with a molecular association of AGT T235.

Subsequently, they found that more expression of the

235Thr variant in 235Met/Thr heterozyotes might be

related to first trimester atherotic changes before pre-

eclampsia (Morgan et al. 1997). Later, a study conducted

by Levesque et al. (2004) among 847 French Canadian

pregnancies (180 cases of preeclampsia, 310 cases of

essential hypertension, 357 cases of normotensive control

subjects) reported that AGT Thr174Met was markedly

associated with preeclampsia and A-Met-Thr (G1035A-

Thr174Met-Met235Thr) haplotype was related to a

2.1-fold increased risk of preeclampsia. However, research-

ers also do not agree on the association between the AGT

polymorphism and preeclampsia. The studies performedby Kaur et al. (2005), Kobashi (2006), and Zafarmand

et al. (2008) revealed an obvious association between

Met235Thr (AGT) and hypertension in preeclampsia,

which clearly contradicts the findings ofBashford et al.

(2001) and Galao et al. (2004). The studies of the the

Genetics of Preeclampsia Consortium (GOPEC 2005)

andAkbar et al. (2009)also reported inconsistent results.

As for 83A/G Ren genetic variants, the positive relationship

with preeclampsia has been assumed to be very weak.

Despite all these conflicting evidences, Procopciuc

e t a l. (2011) proved that the risk of preeclampsia

increased significantly for women homozygous forMet235Thr AGT, I/D ACE, A116C AT1R, and 83A/G REN

polymorphisms. More than that, their results suggested

that there was a relationship between mutated Met235Thr

AGT and Thr174Met AGT genotypes and lower gestational

age at delivery and/or birth weight. Furthermore, the most

original and inspiring part of their work is that they first

analyzed the interaction of seven maternal/newborn

RAS genotypes and their connection with the risk of

preeclampsia: independently of the maternal genotype,

newborn Thr174Met AGT and A1166C AT1R poly-

morphisms were associated respectively with a 1.53- and

1.22-fold risk of preeclampsia, which also increased

substantially if both the mother and newborn suffered

from one of the Met235Th AGT, I/D ACE, A1166C AT1R,

and 83A/G REN polymorphisms. This study confirmed

the hypothesis that mutated newborn RAS genes and the

interaction of RAS maternal/newborn genotypes make

an important contribution to the pathogenesis of pre-

eclampsia in mothers, as well as to intrauterine growth

retardation (Procopciuc et al. 2011). Although most






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molecular genetic studies of preeclampsia to date have

focused on maternal susceptibility genes, maternalfetal

interactions have attracted ever-increasing attention

and will be the direction of future studies. The summaryof discussed candidate genes in preeclampsia is shown

inTable 2.

miRNA related to RAAS in preeclampsia

The discrepancies between studies decrease dramatically

when it comes to subpopulations defined by ethnic origin

(Hirschhorn et al. 2002, Sethupathy et al. 2007). For

example, the literature search bySethupathy et al. (2007)

suggested a clear association of the 1166C allele with

hypertension in several such major subpopulations as

pregnancy hypertension. The increased frequency ofC1166A/C polymorphism has been correlated with

preeclampsia. However, the discordance remains about

the physiological significance of this polymorphism,

probably due to its location in the 30-UTR of human

AT1Rgenes.

Recently, miRNA seems to provide feasible bio-

chemical mechanisms. miRNAs are w21-nucleotide

small noncoding RNA mainly involved in such post-

transcriptional gene regulation as silencing gene

expression by basepairing to their targets within the

3 0-UTR in the complementary sequences (Kloosterman &

Plasterk 2006). Interestingly, more studies have suggested

that SNPs in the 3 0-UTR can affect gene regulation by

interfering with miRNA binding (Doench et al. 2003,

Hutvagner et al. 2004, Abelson et al. 2005, Clop et al.

2006). miR-155, a typical multifunctional miRNA, is a case

in point. Martinet al. for the first time examined whether

miRNAs play a role in regulating components of the

RAS. It has been demonstrated that miR-155 binding to

the 3 0-UTR of human AT1R mRNA can translationally

repress the endogenous expression of human AT1R and

significantly reduce ANG II-induced ERK 1/2 activation

(Martin et al. 2006, Zheng et al. 2010, Zhu et al. 2011).

Moreover, further laboratory experiments showed that the

human AT1RC1166A/C polymorphism overlaps with the

miR-155 target site in the 3 0-UTR of this gene and the

C1166C allele decreases the ability of miR-155 to interact

with the cis-regulatory site, leading to attenuation of

miR-155 silencing function and enhancement of AT1R

expression (Martin et al. 2006, 2007), similar to another

simultaneous study conducted by Sethupathy etal. (2007).

Besides, an additional hint was provided suggesting that

miR-155 could participate in blood pressure regulation

from low blood pressure. Overexpression of miR-155

resulted in underexpression of AT1R in fibroblasts of

homozygous twins discordant for trisomy 21 with the

observed low blood pressure. These data strengthened the

hypothesis about the association betweenC

1166C alleleand hypertension. Furthermore, Ceolotto et al., conduct-

ing a casecontrol trial among young untreated hyperten-

sives, reported that compared with subjects with AA and

AC genotypes, patients homozygous for the 1166C allele

experienced a significant decline in miR-155 expression

but a reverse trend in AT1R protein expression and blood

pressure. Taken together, miR-155 seems related to

hypertension via regulating the component of RAS. The

abrogation of miR-155 binding suggests at least a very

compelling mechanism for the correlation of 1166C with

abnormal blood pressure. It is rational to hypothesize

an inverse correlation between miR-155 and AT1R inpreeclampsia, based on the aberrant AT1R protein

expression and intractable hypertension observed in

preeclamptic women.

However, the expression of miR-155, either upregu-

lated or downregulated, differed in diverse tissues of

preeclampsia. In 2007, a cross-sectional, casecontrol

study by Pineles et al. for the first time indicated that

in placenta of a preeclampsia plus small-for-gestational

age (SGA) group, the expression of miR-155 was much

higher than in the control group with spontaneous

preterm labor and delivery (PTL; Pineles et al. 2007).

Later,Zhanget al. (2010)found a similar trend in miR-155greatly upregulated in preeclampsia placenta. By contrast,

Chenget al. (2011)demonstrated that severely preeclamp-

tic pregnant women had less mature miR-155, yet a much

higher expression of AT1R in their human umbilical

vein endothelia cells (HUVECs) compared with healthy

puerperant women. Similarly, a recent study indicated

that overexpression of miR-155 in HUVECs (Zhu et al.

2011) suppressed the expression of AT1R via interacting

Table 2 Summary of candidate genes in preeclampsia

reported by different groups

Gene

symbol

Map

location

Gene

ID Polymorphism

Remarks

elevated

CYP11B2 8q21q22 1585 K344C/T Aldosterone

concentrationACE 17q23.3 1636 I/D(intronic) I/D allele with ACE

activity

AT1R 3q24 185 A1166C ATI receptor

upregulation

AGT lq42.2 183 M234T,T174M Abnormal spiral

artery remodeling

Renin lq32 5972 Placental vascular

contraction






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with the AT1R mRNA 3 0-UTR, leading to repression of

ANG II-induced signal transduction in comparison with

non-translated or mutant-miR-155-transfected cells. The

reasons for these discrepancies probably lie in the

disparate mechanisms by which miR-155 contributes to

preeclampsia. In placenta, both luciferase assays and

transfection assays experimentally corroborated that

increased miR-155 targeted the 3 0-UTR of cysteine-rich

protein 61 (CYR61), a molecular regulating placental

vascular sufficiency, leading to a deficiency in CYR61

level and placental ischemia (Zhang et al. 2010). Despite

elevated AT1Rs and an aberrant miR-155 level, little

research has reported on the relationship between them

in preeclampsia. Nevertheless, further studies remain

necessary in the future. By contrast, when it comes to

vascular remolding and dysfunction, apart from HUVECs,

miR-155 overexpression in rat aortic adventitial fibro-

blasts (AFs) interacted directly with AT1R mRNA 30

-UTR,resulting in decreased AT1R, and attenuated ANG II

-induced AF phenotypic differentiation into myofibro-

blasts (Zheng et al. 2010). Zheng et al. found that adult

spontaneously hypertensive rats characterized themselves

by reduced miR-155 in the aorta accompanied by negative

correlation with blood pressure (Xu et al. 2008). The

expression of miR-155 seems negatively related to blood

pressure and vascular damages (Urbich et al. 2008).

Therefore, aberrant miR-155 might be correlated with

the pathology of preeclampsia via different mechanisms.

But overall, it remains unknown whether miR-155

expression was related to AT1R genetic polymorphismsin preeclampsia.

Perspective

Epigenetics is the study of the alteration of gene func-

tion without a change in the DNA sequence. Recent

evidence from emerging research suggest a possibility

that epigenetic dysregulation, especially abnormal DNA

methylation, might increase preeclampsia susceptibility

(Chelbi & Vaiman 2008). Moreover, compared with classic

mechanisms for miRNAs regulating gene expression,

specific miRNAs called epi-miRNAs target effectors ofsuch epigenetic machinery as DNA methyltransferase,

thereby influencing gene expression controlled by epi-

genetic factors, rather than through mRNA degradation

and mRNA translational inhibition (Chelbi et al. 2007).

A recent study suggested that altered global DNA methyl-

ation patterns in placenta were found to be associated

with maternal hypertension in preeclampsia (Kulkarni

et al. 2 011). Early research among patients with

preeclampsia or intrauterine growth restriction (IUGR)

suggested that much more gene-specific hypomethylation

like TIMP3 a gene involved in cell growth, invasion,

migration, transformation was found in early-onset

preeclamptic placentas (Yuen et al. 2010). More interest-

ingly, alterations in promoter DNA methylation of genes

of RAAS were observed in the fetal programming of

hypertension in animal models (Bogdarina et al. 2007,

Goyal et al. 2010). For example, the AT1b receptor gene

under methylation in the adrenal gland results in higher

expression of the AT1b receptor and increased adrenal

angiotensin responsiveness in the maternal low-protein

diet rat model of programming (Bogdarina et al. 2007).

In addition, human ACE expression level was found to

be under a strong DNA methylation characterized by

cell-type-specific and tissue-specific regulations (Riviere

et al. 2011). Moreover, it has been substantiated that

several miRNAs, such as miR-130a, miR-181a, miR-222,and miR-220, seem prevalent in the placenta and serum of

severe preeclamptic women (Bogdarinaet al. 2007,Pineles

et al. 2007, Zhu et al. 2009). Further investigations are

required to decipher the precise binding sites of aberrant

miRNAs to targeted genes. Nevertheless, few direct

evidences have been found to identify the possibility of

miRNA targeting the sites of RAAS gene mRNA. Given

that preeclampsia is often accompanied by IUGR and

shares similar both maternal and fetal pathology with

administration of a low-protein diet during pregnancy,

epi-miRNA may provide a feasible mechanism to explain

the abnormal DNA methylation and miRNA expressionlevel in preeclampsia.

Summary

RAAS is the primary system regulating blood fluids and salt

and water balance. During normal pregnancy, all com-

ponents of RAAS show compensatory and protective

alterations. But overall, the balance was broken in

preeclampsia. Various studies in different populations

have identified both maternal and fetal polymorphisms

associated with preeclampsia. Furthermore, at a post-

transcriptional level, such miRNA as miR-155 might

participate in pathology of preeclampsia via binding to

the targeted sites of genes and regulating RAAS expression.

However, controversial results hinder research from a

definitive conclusion on the influence of genetic poly-

morphisms due to variations in ethnic population, genetic

basis, genetic misclassification, preeclampsia criteria,

sample sizes, detective methods, and so on. In the future,

meta-analyses, especially cumulative meta-analyses, may






10/14

give a more determined perspective of underlying effects.

Of all the limitations, small sample sizes encumber

researchers most regarding deeper statistical analyses

based on the principles of ratios of the amount of

parameters to the subject sizes. In summary, many

promising findings were reported about the interactions

with genetic polymorphisms and RAAS alterations in

preeclampsia but remain to be replicated.

Declaration of interest

The authors declare that there is no conflict of interest that could be

perceived as prejudicing the impartiality of the review.

Funding

This work was supported by the grants from the Natural Sciences

Foundation of China (NSFC) 81070263, KZ201110025023 from Science and

Technology Plan Project of Beijing Municipal Education Commission.

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