The Role of the Renin–Angiotensin– Aldosterone System in Preeclampsia: Genetic Polymorphisms and Microrna

J YANG and others Role of RAAS in preeclampsia 50:2 R53–R66 Review

The role of the renin–angiotensin– aldosterone system in preeclampsia: genetic polymorphisms and microRNA

Jie Yang1, Jianyu Shang1, Suli Zhang1, Hao Li1 and Huirong Liu1,2 Correspondence 1Department of Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 Xitoutiao, You An should be addressed to H Liu Men, Beijing 100069, People’s Republic of China 2Department of Physiology, Shanxi Medical University, Taiyuan, Email Shanxi 030001, People’s Republic of China [email protected]

Abstract

The compensatory alterations in the rennin–angiotensin–aldosterone system (RAAS) Key Words contribute to the salt–water balance and sufﬁcient placental perfusion for the subsequent " Pre-eclampsia well-being of the mother and fetus during normal pregnancy and is characterized by an " Renin–angiotensin system increase in almost all the components of RAAS. Preeclampsia, however, breaks homeostasis " Polymorphism and leads to a disturbance of this delicate equilibrium in RAAS both for circulation and the " Genetic uteroplacental unit. Despite being a major cause for maternal and neonatal morbidity and " microRNA 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 Journal of Molecular Endocrinology 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 30-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 Journal of Molecular are needed to avoid the interference from different variations. Endocrinology (2013) 50, R53–R66

Introduction

Preeclampsia, characterized as hypertension (O140/90 mmHg) effects to mothers and their children. According to recent after 20 weeks’ gestation accompanied by proteinuria epidemiological studies, 5–7% of pregnant women in the (O300 mg/l), represents a major cause of maternal and world have suffered from this disease (Kuc et al. 2011). neonatal morbidity and mortality, leading to devastating Various as the theories for pathogenesis of preeclampsia

http://jme.endocrinology-journals.org Ñ 2013 Society for Endocrinology Published by Bioscientiﬁca Ltd. DOI: 10.1530/JME-12-0216 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 06:56:11AM via free access Review J YANG and others Role of RAAS in preeclampsia 50:2 R54

are, the exact underlying molecular mechanisms remain aldosterone (ALD). Through a major activation of AT1R unclear but are likely to be multifactorial: endothelial and then the primary aldosterone-synthesizing enzyme cell dysfunction, excessive vasoconstriction (Roberts & (CYP11B2), in the zona glomerulosa of the adrenal cortex, Gammill 2005), inflammation, immunological disorder ANG II affects the production of ALD synthesis, which (Hubel et al. 2007), etc. Of the multifactorial impact plays a critical role in the regulation of salt and water factors, the renin–angiotensin–aldosterone system (RAAS) retention and excretion to maintain sufficient blood fluids serves as the major cause for shallow trophoblast invasion and electrolyte balance. and impaired spiral artery remodeling, which are the most It has been confirmed that the components of RAS are paramount and fundamental pathological alterations not unique to the kidney but are synthesized in many followed by a series of complications. The compensatory tissues, among which one of the major local RAS during and delicate changes of RAAS during normal pregnancy pregnancy is in the uteroplacental unit (placenta also are hard to counterbalance for preeclamptic women, named fetal origin and decidua named maternal origin) resulting in body capillary constriction, renal damages, (Shah 2006). Since the first-time pro-renin, AGT, ACE, disorders of salt and water balance, etc. However, the ANG II and ANG I, AT1R were identified in fetal placental etiology of this dysfunction requires further explorations. tissues (Li et 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 There exists both a classical RAAS and a local human third trimester decidual cells also have demon- renin–angiotensin system during pregnancy strated the presence of AGT and renin (Li et al. 2000). The RAAS contributes to blood pressure regulation Other studies of the decidual spiral arteries have indicated and body fluid through a series of enzymatic reactions the expression of AGT, renin, ACE, and AT1R (Morgan induced by its primary components: renin, angio- et al. 1998a,b). Moreover, it has been demonstrated that tensinogen (AGT), angiotensin-converting enzyme immunocytochemical expression of ANG (1–7) and ACE2 (ACE), angiotensin I (ANG I), angiotensin II (ANG II), was widely distributed throughout the human fetal angiotensin a receptor type I (AT1R), and angiotensin placental unit during gestation (Valdes et al. 2006, Neves receptor type 2 (AT2R). In response to low blood pressure et al. 2007). Therefore, all the necessary components of and low circulating sodium chloride, renin, synthesized RAS have been found both in maternal decidua and in and secreted by juxtaglomerular cells of the afferent renal the fetal placental tissues. arterioles, catalyzes the cleavage of AGT made in the liver Journal of Molecular Endocrinology to ANG I. This is the rate-limiting step of the renin– Compensatory regulation of RAAS during angiotensin system (RAS) cascade. Then, this ten amino pregnancy acid peptide, without any biological function as we presently know, is cleaved by ACE, which is made During normal pregnancy, both body fluid and the RAAS primarily in lung endothelium, into ANG II, a biologically undergo major changes. There is a marked enlargement of active eight amino acid molecule. ACE2, a homolog of plasma volume that starts in the first trimester, accelerates ACE, is a new component of RAS and can cleave a single in mid-gestation, and stabilizes after around the 34th week residue from ANG II to form angiotensin (1–7) (ANG of gestation (Pirani et al. 1973). In other words, this new (1–7)), or from ANG I to angiotensin (1–9) (ANG (1–9)) steady state in pregnancy reflects a downward resetting of (Anton & Brosnihan 2008), whose functions include a the osmolarity thresholds for thirst sensation and vaso- vasodilator response and antidiuresis in water-loaded pressin release, which finally leads to an increase in salt animals. Therefore, ACE2, ANG (1–7), and ANG (1–9) are and water strengthening placental perfusion to protect regarded to modulate the effects of RAS on vascular tone, the pregnant woman and her fetus (Escher & Mohaupt neutralizing excessive contraction. There exist two major 2007). As the most principal part in the renal control of types of angiotensin receptors: AT1R and AT2R, both of body fluid, nearly all the components of RAAS experience which belong to seven transmembrane G-protein-coupled an increase except ACE, the only component decreasing receptor families, though their distributions and functions or leveling off at the nonpregnant concentration (Merrill are totally different. Via activation of AT1R or AT2R, et al. 2002). An early increase in renin is observed due to ANG II is regarded as a well-known versatile effector the local release by maternal decidua and ovaries (Hsueh involved in vasoconstriction, sympathetic activity, cell et al. 1982), and the growth of circulating estrogen viability, and the release of different molecules, such as generated by fetus placenta promotes the AGT synthesis

in the liver, which leads to obvious rises in serum ANG II Table 1 Serum RAAS levels in normotensive and preeclamptic (Brown et al. 1988). ALD level shows an upward trend pregnancies vs nonpregnancies. Pregnancy is characterized by mainly corresponding to the requirement for volume marked alterations of RAAS. In pregnancy, the increase in expansion. Meanwhile, in both plasma and urinary levels, almost all RAAS components leads to a marked enlargement of there is also an increase both in ANG (1–7) and ACE2 plasma volume for sufficient placental perfusion. On the other (Valdes et al. 2001, Oudit et al. 2003, Turner 2003). hand, in preeclampsia, the gravid experiences hypertension Furthermore, in rat pregnant models, a study conducted accompanied by damaged control of salt–water balance mainly by Levy et al. (2008) indicated that the uterus and because of elevated AT1R activity and sensitivity neutralizing placentas contributed to Ace2 expression and activity decreased ANG II concentration during preeclampsia. The placenta was the foremost total contributor, although the kidney was responsible for the Normotensive Preeclamptic RAAS componets pregnancy pregnancy highest levels of ACE2 activity. They found that during CC K pregnancy, ACE abundance in reproductive organs during AGT Renin CC C the third trimester of pregnancy was commensurate with Renin activity CC Z/K a systemic vasodilatory state both in normotensive and in ALD CC K CC Z K hypertensive rats. ACE activity in the uterus was affected ANG II / ANG II activity KCC by salt-loading. These studies demonstrate the importance ANG (1–7) CC K of transient overexpression of ACE2 and its elevated ACE K Z/K CC K activity in modulating systemic and local hemodynamics ACE2 ACE2 activity CC K in the uteroplacental unit during pregnancy. However, AT1R Z CC we know little about the underlying exact mechanisms. Although ANG II levels increase during pregnancy, CC, significantly increased over nonpregnancy; C, slightly increased over nonpregnancy; Z, same as nonpregnant; K, decreased compared with normotensive pregnant women are less responsive to its nonpregnancy. vasopressor effects, which was substantiated by the historic study conducted by Assali & Westersten (1961) et al. 2001, Merrill et al. 2002); stranger still, there is a showing that the required ANG II concentration of a relatively higher level of ALD for the given level of renin pregnant woman is twice that needed in a nonpregnant (Gallery & Brown 1987) and worse, pregnant women are woman to achieve the same vasomotor response. This highly sensitive to the pressor effects of ANG II partly due reduced ANG II sensitivity is considered to be due to the to heterodimerization of AT1R (Quitterer et al. 2004, Journal of Molecular Endocrinology increased progesterone and prostacyclins (Gant et al. Abdalla et al. 2005). As for local uteroplacental RAS, there 1980), as well as a little inactivation of AT1R by reactive are some various and controversial results: recently, oxygen species (ROS; Abdalla et al. 2001). Herse et al. (2007) argued that excessive expression of the AT1R receptor in maternal deciduas is the only change Changes in both circulating RAAS and local observed in local RAS, without any increase in renin RAS during preeclampsia production in decidua of preeclamptic patients. By contrast, Shah et al. (2000) demonstrated an increase in Women with preeclampsia suffer from an utterly different renin level in the deciduas vera of preeclamptic women. RAAS state (Table 1) and develop a much poorer control of A recent clinical trial performed by Anton et al. (2008) sodium loading and a substantial fluctuation of sodium suggested that in the chorionic villi of preeclampsia level in sera with avid retention of sodium and slow excretion of additional sodium loads, when compared patients, an essential part of the placenta responsible for with normotensive pregnant women who have much regulating nutrient and oxygen exchange between the better tolerances of sodium intake and slight changes in mother and the fetus, ANG II levels and AT1R mRNA were either weight or plasma volume (Symonds et al. 1975, significantly higher despite a decrease in circulating Herse et al. 2007). This implies that there is a dysfunction ANG II when compared with normal pregnancies. of salt–water balance that is dominated mainly by ALD. Furthermore, in murine models of antenatal maternal Moreover, compared with the increase in RAAS com- hypoxia responsible for the development of preeclampsia, ponents in normotensive pregnancy, the circulating levels such stress elevated the expression of AGT and ACE by of renin, ANG I, ANG II, ANG (1–7), and ALD are much post-transcriptional mechanisms in murine placenta lower, yet with little fluctuation of ACE levels (Granger (Goyal et al. 2011). Another symptom leading to

preeclampsia is pregnancy-induced hypertension, of observed in different geographic, socioeconomic, and which the rat model suggested that ANG (1–7) concen- racial features (Hocher et al. 2008). Researchers, for trations decreased both in the uterus and placenta, so did instance, reported that compared with the offspring or Ace2 mRNA levels (Neves et al. 2008). The possible reasons relatives of normotensive pregnancies, daughters of for this divergence involve the different sample sizes, preeclamptic mothers suffered from much higher inci- chosen tissues, and deﬁning criteria for preeclampsia, dence of risk for the disease ranging from 20 to 40%, 11 to which suggests that it is necessary to conduct further 37% for sisters of preeclamptic women, and 22 to 47% in investigation. In summary, preeclampsia is characterized twin studies (Mogren et al. 1999, Esplin et al. 2001, Hocher by a series of signiﬁcant alterations in RAAS worthy of et al. 2008). Studies also showed paternal contributors deeper research (Fig. 1). 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 Genetic mutations in preeclampsia play among males who previously fathered a preeclamptic a big role pregnancy with another partner (Lie et al. 1998). Trying Right now, we still know little about the exact reasons to separate the effect of maternal and fetal genetic factors for the dysfunction of RAAS in preeclampsia, although from environmental factors, Cnattingius et al. (2004) several pathophysiological mechanisms have been pro- suggested that via population-based Swedish Birth and posed including endothelial damage, oxidative stress, and Multi-Generation Registries, genetic factors accounted autoimmunity. Yet inspiringly, from an epidemiological for more than 50% of the liability to preeclampsia, point of view, various genetic and environmental factors maternal genes may contribute more than fetal genes have been considered to contribute to the pathogenesis and genetic interaction effects between spouses. Naturally, of preeclampsia due to a strong familial predisposition 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 AGT Renin the importance of RAAS in preeclampsia, this review ACE2 will be limited to the current views on genetic mutations ANG (1–9) ANG l ACE in RAAS. ACE2 ANG (1–7) ANG ll Vasocontraction Journal of Molecular Endocrinology Sensitivity Genetic polymorphisms associated with ANG (1–7)-R AT1 R decreased ALD level Mas

Aldosterone Deﬁciency of ALD, a paramount hormone regulating

Vasodilation body ﬂuid, has been considered to be involved in the

Adjustment of development of reduced placental perfusion and hyper- salt–water balance tension leading to a variety of factors that cause widespread dysfunction of the maternal vasculature Uteroplacental perfusion (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

Intrauterine growth retardation ischemia (Gallery & Brown 1987, Roberts & Cooper 2001, Takeda et al. 2002). Therefore, the reduced circulating

Figure 1 volume circumscribes placental blood supply, ﬁnally Despite a signiﬁcant decrease in most components, elevated sensitivity inducing an elevated blood pressure during preeclampsia. of AT1R and its increased amount seem to account for hypertension and Compared with normal pregnancies, preeclamptic women intrauterine growth retardation in preeclampsia. The red arrows indicate an increase in concentration while the blue arrows indicate a decrease in are proven to experience much lower levels of circulating concentration. ALD (Shojaati et al. 2004).

CYP11B2 activity is impaired in preeclampsia partly hypertension in Chilean residents (Fardella et al. 1996). because of genetic polymorphisms. CYP11B2, a multi- The other was V386A-CYP11B2 polymorphism that had enzyme complex sharing 93% homology to CYP11B1, been reported, compared with 4% in normotensive comprised three enzymatic reactions conducting the pregnancies, to show up in 18% of patients with essential last but most important in ALD synthesis, whose activities hypertension closely related to preeclampsia (Pascoe can be quantified separately through the determination et al. 1992), although it solely appeared in preeclamptic of urinary steroids. Compared with the increased tetra- women in Kushiar’s own study. K hydroaldosterone (TH-Aldo) during normal pregnancy, Recently, the 344C/T CYP11B2 polymorphism a metabolite of urinary ALD, preeclampsia is charac- disrupting a putative steroidogenic factor-1 site (SF-1) in terized by a higher level of TH-Aldo’s immediate precursor CYP11B2 has attracted more attention and has been – 18-OH-tetrahydrocorticosterone (18-OH-THA) cortico- reported as a loss-of-function mutation associated with a sterone -and lower levels of TH-Aldo, suggesting com- high risk of preeclampsia, compared with the gain- prised ALD synthase (Fig. 2; Shackleton 1993, Shojaati of-function in high ALD-to-renin ratio alleles in normal pregnancies (Bauknecht et al. 1982, Lindheimer & Katz et al. 2004). To characterize the jeopardized CYP11B2 1992, Wacker et al. 1995). The T-allele polymorphism in (Shojaati et al. 2004), Shojaati et al. demonstrated that the the 50-flanking region of the CYP11B2 gene has been reduced ALD synthesis was due to diminished methyl reported to be more relevant in hypertensives than in oxidase activity with which genetic polymorphisms normotensives and has also been related to increased appeared to be associated. Based on the altered urinary ALD levels (Davies et al. 1999, Tamaki et al. 1999, Komiya steroid profile, they found two of five exon mutations et al. 2000, Poch et al. 2001, Nicod et al. 2003, Escher associated with an increased risk of preeclampsia – R173K et al. 2009). Nicod et al. (2003) were the first to posi- and V386A-CYP11B2. R173K CYP11B2 polymorphism was tively associate the K344/CT CYP11B2 polymorphism slightly less frequent in preeclampsia, as it had been with increased ALD in selected hypertensive patients. reported previously (Portrat-Doyen et al. 1998), whereas Recently, a study performed by Escher et al. (2009) other studies claimed that it was related to low renin confirmed the hypothesis of the correlation of higher ALD availability in normal pregnancies with lower maternal blood pressure, and heterozygosity for SF-1 Cholesterol preferably in preeclampsia corresponded to hypertension CYP11A1/StAR Pregnenotone and deficiency in placental infusion. In other words, the

Journal of Molecular Endocrinology HSD3B2 prevalence of gain-of-function homozygosity for SF-1 Urinary steroid metabolites Peogesterone determined prevented pregnancies from developing preeclampsia. CYP21A2 Interestingly, many studies have reported the low DOC, THDOC 11-Deoxycorticosterone 11-Hydroxylase (CYP11B1) expression of high ALD-to-renin ratio variants in pre-

THB, THA Corticosterone eclampsia in the healthy, normotensive, nonpregnant 18-Hydroxylase CYP11B2 subjects, which strongly corroborates with the notion that 18,OH-THA 18-Hydroxycorticosterone K344C/T CYP11B2 polymorphism variants, instead of SF- 18-Oxydase 1-344T/T CYP11B2 genotype, predisposed women to TH-Aldo Aldosterone preeclampsia, as well as facilitating any additional contributing factors to the increased risk of developing

Figure 2 preeclampsia (Lim et al. 2002, Nicod et al. 2003, Escher Adrenocortical steroidogenic pathway for ALD biosynthesis. StAR is et al. 2009). As reported in a research study conducted by paramount for the rate-limiting step of movement of cholesterol into the Procopciue et al. (2010), women with CC344 CYP11B2 mitochondria, where cholesterol is cleaved by CYP11A1 to pregnenolone. Then the compound is catalyzed by HSD3B2, CYP21A2, and CYP11B2 into tended to experience an increased risk of preeclampsia ALD. Urinary steroid metabolites can be quantified to assess the enzyme (3.21 vs 1.29 of those with CT344 CYP11B2), of which the activities of CYP11B2 consisting of three different enzymatic reactions. tendency appeared in mild preeclampsia and severe In preeclampsia, the decreased TH-Aldo level accompanied by elevated 18-OH-THA indicates impaired CYP11B2 activity, specifically 18-oxidase preeclampsia, 1.49 and 2.01 with a significant statistical activity. DOC, 11-deoxycorticosterone; THDOC, tetrahydro-11-deoxycortico- difference respectively. They also found the CC344 sterone; THB, tetrahydrocorticosterone; THA, tetrahydro-11-dehydrocortico- CYP11B2 polymorphism was related to curtailed delivery sterone; 18-OH-THA, 18-OH-tetrahydrocorticosterone; TH-Aldo, tetrahydroaldosterone. The red arrows indicate an increase in concentration gestation and decreased birth weight of babies. Interest- while the blue arrows indicate a decrease in concentration. ingly, still, for a woman positive for M235T AGT or I/D

ALD (see below), a much higher risk of preeclampsia was and the ID genotype with middle levels (Rigat et al. 1990, observed if she had a C344T CYP11B2 polymorphism. 1992). The reason for the higher ACE levels in the D allele However, some studies indicated a lack of association is partly due to the silencer sequence in the 1 allele (Choi (Mulatero et al. 2000, Percin et al. 2006). A negative et al. 2004). Furthermore, Ueda et al. (1995) found that DD relationship of K344C/T CYP11B2 with pregnancy- carriers suffered from a more marked increase in venous induced hypertension closely related to preeclampsia concentration of ANG II and blood pressure compared was supported by a recent case–control study among 100 with II carriers after injection of ANG I. In consideration women in 2011 (Remı´rez-Salazar et al. 2011). Despite the of the contribution of high ACE to hypertension (Wilson reduced serum ALD levels in gestational hypertensive et al. 1991, Nogueira et al. 2009), naturally, there is the women, neither was the genotype of K344T/C of favored hypothesis of a functional polymorphism involved CYP11B2 related with gestational hypertension nor with in pathophysiological conditions of hypertension. Based ALD levels at delivery. A direct comparison of these on clinical studies, some researchers failed to ﬁnd a polemical results is often limited by the missing infor- signiﬁcant association between the I/D polymorphism mation on primiparity, the ethnic divergence between and hypertension (Jeunemaitre et al. 1992, Schmidt et al. different study groups, and the concern for any other 1993, Agachan et al. 2003), whereas several other studies patient abnormalities, such as diabetes. Moreover, pre- reported a positive association between the D allele and eclampsia is regarded as a multifactorial disease with high blood pressure (Iwai et al. 1994, Schunkert et al. 1994, various factors contributing to the different extents, of Staessen et al. 1997, Giner et al. 2000). This is probably which genetic divergence is likely to play a large role. because it is necessary to perform sensitivity analyses in Moreover, decreased ALD concentration might be subgroups based on gender, ethnicity, mean ages, and attributed to altered activity of the mineralocorticoid genotyping methods. According to these data, there was a receptor (MR), due to the binding of ALD and MR substantial relationship between the D allele and hyperten- conducting the major functions of ALD in renal sodium sion in women and in Asians (Kim et al. 2004). Further- reabsorption and potassium excretion. Despite the more, with the help of transgenic mice models of these increased competitive combinations of other hormones three functional copies of the ACE gene (DD, DI, II), Krege against ALD in preeclampsia (Myles & Funder 1996), either et al. (1997) found that there was no marked difference gaining or loss-of-function mutations of MR genes such in blood pressure between DD type and II type, although as the S810L mutation appeared to be associated with the the higher activity of ACE in serum was easily detected in alteration of ALD in preeclampsia (Geller et al. 1998, 2000, the DD type. This discrepancy suggests the combination

Journal of Molecular Endocrinology Pearce et al. 2003, Procopciue et al. 2010). However, the of ACE gene expression and additional environmental or overall assumption favored by most scientific research is genetic factors would greatly affect blood pressure. that the genetic polymorphisms of MR are rare and cannot The consequence of ACE in blood pressure by be a factor significant enough to articulate the frequency regulating the generation of ANG II has stimulated ever of preeclampsia (Nicod et al. 2003, Escher et al. 2009), more investigations on the role of the ACE I/D poly- although this assumption is supported by observations morphism in the pathogenesis of preeclampsia. The in very small subsets of preeclamptic patients by other results are conflicting, presumably attributable to groups (Schmider-Ross et al. 2004, Tempfer et al. 2004). differences in study population, ethnics, genetic basis, and sample size. It has been assumed that lack of ACE polymorphism in preeclampsia association between the ACE I/D polymorphism appeared more in Koreans (Kim et al. 2004), Colombians (Serrano The ACE I/D polymorphism seems to be related to et al. 2006), Greeks, and Black South African women hypertension. Rigat et al. (1990) made a striking discovery (Bouba et al. 2003, Roberts et al. 2004, Akbar et al. 2009). after performing deeper studies of the ACE gene for the Recently, in a meta-analysis using data from 17 studies detection of the well-known polymorphism involving the (Shaik et al. 2011), Shaik et al. argued that the presence of presence (insertion, I) or absence (deletion, D) of a 287 bp the ACE I/D polymorphism was not related to increased sequence of DNA in intron 16 of this gene, located on risk of preeclampsia. In southeastern Iran (Salimi et al. the long arm of chromosome 17(17q23) with 26 exons 2011), northern India (Aggarwal et al. 2011), and Turkey and 25 introns. More evidence corroborate that the (Morgan et al. 1998a,b, Bereketoglu et al. 2012), however, DD genotype is commensurate with higher ACE levels, the presence of the D allele of the ACE gene was related to whereas the II genotype is associated with lower ACE levels increased risk of preeclampsia. Uma et al. (2010) found

that the DD genotype of ACE was related to early-onset the risk of preeclampsia. As for AGT polymorphisms, the preeclampsia, although no marked changes in RAS were exon 2 polymorphism M 235T has been extensively detected. A recent study by Bereketoglu et al. (2012) also explored (Kobashi et al. 1999, Suzuki et al. 1999). Ward suggested a higher incidence of the DD genotype in et al. (1993) observed a significant association of pre- Turkish preeclampsia patients in all the three models – eclampsia with a molecular association of AGT T235. codominant, recessive, and dominant. Meanwhile, based Subsequently, they found that more expression of the on 30 case–control studies, a meta-analysis by Chen et al. 235Thr variant in 235Met/Thr heterozyotes might be (2012) showed a strong relationship between the DD related to first trimester atherotic changes before pre- genotype of ACE and a higher risk of pregnancy eclampsia (Morgan et al. 1997). Later, a study conducted hypertensive disorders, especially for Asians and Cauca- by Levesque et al. (2004) among 847 French Canadian sians. Furthermore, Rahimi et al. (2013) confirmed that the pregnancies (180 cases of preeclampsia, 310 cases of ACE D allele and DD genotype were more associated with essential hypertension, 357 cases of normotensive control increased risk of mild preeclampsia (1.99- and 2.34-fold subjects) reported that AGT Thr174Met was markedly respectively) than severe preeclampsia (1.61- and 1.56-fold associated with preeclampsia and A-Met-Thr (G1035A- respectively), similar to the results of the study by Mando` Thr174Met-Met235Thr) haplotype was related to a et al. (2009). These results substantiated the theory that 2.1-fold increased risk of preeclampsia. However, research- severe and mild preeclampsia patients are characterized by ers also do not agree on the association between the AGT genetic heterogeneity (Oudejans et al. 2007). Furthermore, polymorphism and preeclampsia. The studies performed they demonstrated that the ID genotype of ACE is associated by Kaur et al. (2005), Kobashi (2006), and Zafarmand with lower total antioxidant capacity levels compared et al. (2008) revealed an obvious association between with the II genotype, which suggested the lipid per- Met235Thr (AGT) and hypertension in preeclampsia, oxidation and oxidative stress, known to be involved in which clearly contradicts the findings of Bashford et al. the pathogenesis of preeclampsia, and this might be (2001) and Galao et al. (2004). The studies of the the influenced by polymorphisms in the genes. Moreover, a Genetics of Preeclampsia Consortium (GOPEC 2005) recent study by Procopciuc et al. (2011) showed that a and Akbar et al. (2009) also reported inconsistent results. preeclamptic woman with at least one mutated D-ACE allele As for 83A/G Ren genetic variants, the positive relationship suffered from a higher frequency of maternal complications, with preeclampsia has been assumed to be very weak. a lower gestational age, and lower birth weight babies. Despite all these conflicting evidences, Procopciuc Although ever-increasing human studies are conducted to et al. (2011) proved that the risk of preeclampsia

Journal of Molecular Endocrinology prove a positive association between ACE I/D poly- increased significantly for women homozygous for morphism with preeclampsia, various sample size, genetic Met235Thr AGT, I/D ACE, A116C AT1R, and 83A/G REN basis, and ethnicity, a more appropriate mouse model or polymorphisms. More than that, their results suggested other basic scientific research may offer more information. 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 Genetic polymorphisms in AT1R, AGT, and renin original and inspiring part of their work is that they first analyzed the interaction of seven maternal/newborn Other RAS gene polymorphisms, such as AT1R A1166C, RAS genotypes and their connection with the risk of AGT Met235Thr, AGT Thr174Met, and 83A/G-REN, seem preeclampsia: independently of the maternal genotype, related to preeclampsia. Similarly, studies are diverging newborn Thr174Met AGT and A1166C AT1R poly- on the relationship of AT1R A1166C and preeclampsia – morphisms were associated respectively with a 1.53- and some claiming a higher risk of pregnancy-induced 1.22-fold risk of preeclampsia, which also increased hypertension commensurate with the AT1R A1166C substantially if both the mother and newborn suffered polymorphism (Shanmugam et al. 1993, Hu et al. 2000, from one of the Met235Th AGT, I/D ACE, A1166C AT1R, Seremak-Mrozikiewicz et al. 2005, Procopciuc et al. 2011, and 83A/G REN polymorphisms. This study confirmed Salimi et al. 2011), yet others are failing to report marked the hypothesis that mutated newborn RAS genes and the differences (Morgan et al. 1998a,b,Liet al. 2007) partly due interaction of RAS maternal/newborn genotypes make to the multifactorial character of preeclampsia. Moreover, an important contribution to the pathogenesis of pre- Salimi et al. recently demonstrated a lack of synergistic eclampsia in mothers, as well as to intrauterine growth effects between two alleles of ACE D and AT1R A116C on retardation (Procopciuc et al. 2011). Although most

Table 2 Summary of candidate genes in preeclampsia repress the endogenous expression of human AT1R and reported by different groups significantly reduce ANG II-induced ERK 1/2 activation (Martin et al. 2006, Zheng et al. 2010, Zhu et al. 2011). Gene Map Gene Remarks Moreover, further laboratory experiments showed that the symbol location ID Polymorphism elevated human AT1RC1166A/C polymorphism overlaps with the CYP11B2 8q21–q22 1585 K344C/T Aldosterone miR-155 target site in the 30-UTR of this gene and the concentration C ACE 17q23.3 1636 I/D(intronic) I/D allele with ACE 1166C allele decreases the ability of miR-155 to interact activity with the cis-regulatory site, leading to attenuation of AT1R 3q24 185 A1166C ATI receptor miR-155 silencing function and enhancement of AT1R upregulation AGT lq42.2 183 M234T,T174M Abnormal spiral expression (Martin et al. 2006, 2007), similar to another artery remodeling simultaneous study conducted by Sethupathy et al. (2007). Renin lq32 5972 – Placental vascular Besides, an additional hint was provided suggesting that contraction miR-155 could participate in blood pressure regulation from low blood pressure. Overexpression of miR-155 molecular genetic studies of preeclampsia to date have resulted in underexpression of AT1R in fibroblasts of focused on maternal susceptibility genes, maternal–fetal homozygous twins discordant for trisomy 21 with the interactions have attracted ever-increasing attention observed low blood pressure. These data strengthened the and will be the direction of future studies. The summary hypothesis about the association between C1166C allele of discussed candidate genes in preeclampsia is shown and hypertension. Furthermore, Ceolotto et al., conduct- in Table 2. ing a case–control trial among young untreated hypertensives, reported that compared with subjects with AA and AC genotypes, patients homozygous for the 1166C allele miRNA related to RAAS in preeclampsia experienced a significant decline in miR-155 expression The discrepancies between studies decrease dramatically but a reverse trend in AT1R protein expression and blood when it comes to subpopulations defined by ethnic origin pressure. Taken together, miR-155 seems related to (Hirschhorn et al. 2002, Sethupathy et al. 2007). For hypertension via regulating the component of RAS. The example, the literature search by Sethupathy et al. (2007) abrogation of miR-155 binding suggests at least a very suggested a clear association of the 1166C allele with compelling mechanism for the correlation of 1166C with hypertension in several such major subpopulations as abnormal blood pressure. It is rational to hypothesize

Journal of Molecular Endocrinology pregnancy hypertension. The increased frequency of an inverse correlation between miR-155 and AT1R in C1166A/C polymorphism has been correlated with preeclampsia, based on the aberrant AT1R protein preeclampsia. However, the discordance remains about expression and intractable hypertension observed in the physiological significance of this polymorphism, preeclamptic women. probably due to its location in the 30-UTR of human However, the expression of miR-155, either upregu- AT1R genes. lated or downregulated, differed in diverse tissues of Recently, miRNA seems to provide feasible bio- preeclampsia. In 2007, a cross-sectional, case–control chemical mechanisms. miRNAs are w21-nucleotide study by Pineles et al. for the first time indicated that small noncoding RNA mainly involved in such post- in placenta of a preeclampsia plus small-for-gestational transcriptional gene regulation as silencing gene age (SGA) group, the expression of miR-155 was much expression by basepairing to their targets within the higher than in the control group with spontaneous 30-UTR in the complementary sequences (Kloosterman & preterm labor and delivery (PTL; Pineles et al. 2007). Plasterk 2006). Interestingly, more studies have suggested Later, Zhang et al. (2010) found a similar trend in miR-155 that SNPs in the 30-UTR can affect gene regulation by greatly upregulated in preeclampsia placenta. By contrast, interfering with miRNA binding (Doench et al. 2003, Cheng et al. (2011) demonstrated that severely preeclamp- Hutvagner et al. 2004, Abelson et al. 2005, Clop et al. tic pregnant women had less mature miR-155, yet a much 2006). miR-155, a typical multifunctional miRNA, is a case higher expression of AT1R in their human umbilical in point. Martin et al. for the first time examined whether vein endothelia cells (HUVECs) compared with healthy miRNAs play a role in regulating components of the puerperant women. Similarly, a recent study indicated RAS. It has been demonstrated that miR-155 binding to that overexpression of miR-155 in HUVECs (Zhu et al. the 30-UTR of human AT1R mRNA can translationally 2011) suppressed the expression of AT1R via interacting

with the AT1R mRNA 30-UTR, leading to repression of preeclampsia or intrauterine growth restriction (IUGR) ANG II-induced signal transduction in comparison with suggested that much more gene-specific hypomethylation non-translated or mutant-miR-155-transfected cells. The like TIMP3 – a gene involved in cell growth, invasion, reasons for these discrepancies probably lie in the migration, transformation – was found in early-onset disparate mechanisms by which miR-155 contributes to preeclamptic placentas (Yuen et al. 2010). More interest- preeclampsia. In placenta, both luciferase assays and ingly, alterations in promoter DNA methylation of genes transfection assays experimentally corroborated that of RAAS were observed in the fetal programming of increased miR-155 targeted the 30-UTR of cysteine-rich hypertension in animal models (Bogdarina et al. 2007, protein 61 (CYR61), a molecular regulating placental Goyal et al. 2010). For example, the AT1b receptor gene vascular sufficiency, leading to a deficiency in CYR61 under methylation in the adrenal gland results in higher level and placental ischemia (Zhang et al. 2010). Despite expression of the AT1b receptor and increased adrenal elevated AT1Rs and an aberrant miR-155 level, little angiotensin responsiveness in the maternal low-protein research has reported on the relationship between them diet rat model of programming (Bogdarina et al. 2007). in preeclampsia. Nevertheless, further studies remain In addition, human ACE expression level was found to necessary in the future. By contrast, when it comes to be under a strong DNA methylation characterized by vascular remolding and dysfunction, apart from HUVECs, cell-type-specific and tissue-specific regulations (Rivie`re miR-155 overexpression in rat aortic adventitial fibro- et al. 2011). Moreover, it has been substantiated that blasts (AFs) interacted directly with AT1R mRNA 30-UTR, several miRNAs, such as miR-130a, miR-181a, miR-222, resulting in decreased AT1R, and attenuated ANG II and miR-220, seem prevalent in the placenta and serum of -induced AF phenotypic differentiation into myofibro- severe preeclamptic women (Bogdarina et al. 2007, Pineles blasts (Zheng et al. 2010). Zheng et al. found that adult et al. 2007, Zhu et al. 2009). Further investigations are spontaneously hypertensive rats characterized themselves required to decipher the precise binding sites of aberrant by reduced miR-155 in the aorta accompanied by negative miRNAs to targeted genes. Nevertheless, few direct correlation with blood pressure (Xu et al. 2008). The evidences have been found to identify the possibility of expression of miR-155 seems negatively related to blood miRNA targeting the sites of RAAS gene mRNA. Given pressure and vascular damages (Urbich et al. 2008). that preeclampsia is often accompanied by IUGR and Therefore, aberrant miR-155 might be correlated with shares similar both maternal and fetal pathology with the pathology of preeclampsia via different mechanisms. administration of a low-protein diet during pregnancy, But overall, it remains unknown whether miR-155 epi-miRNA may provide a feasible mechanism to explain

Journal of Molecular Endocrinology expression was related to AT1R genetic polymorphisms the abnormal DNA methylation and miRNA expression in preeclampsia. level in preeclampsia.

Perspective Summary

Epigenetics is the study of the alteration of gene func- RAAS is the primary system regulating blood fluids and salt tion without a change in the DNA sequence. Recent and water balance. During normal pregnancy, all com- evidence from emerging research suggest a possibility ponents of RAAS show compensatory and protective that epigenetic dysregulation, especially abnormal DNA alterations. But overall, the balance was broken in methylation, might increase preeclampsia susceptibility preeclampsia. Various studies in different populations (Chelbi & Vaiman 2008). Moreover, compared with classic have identified both maternal and fetal polymorphisms mechanisms for miRNAs regulating gene expression, associated with preeclampsia. Furthermore, at a post- specific miRNAs called epi-miRNAs target effectors of transcriptional level, such miRNA as miR-155 might such epigenetic machinery as DNA methyltransferase, participate in pathology of preeclampsia via binding to thereby influencing gene expression controlled by epi- the targeted sites of genes and regulating RAAS expression. genetic factors, rather than through mRNA degradation However, controversial results hinder research from a and mRNA translational inhibition (Chelbi et al. 2007). definitive conclusion on the influence of genetic poly- A recent study suggested that altered global DNA methyl- morphisms due to variations in ethnic population, genetic ation patterns in placenta were found to be associated basis, genetic misclassification, preeclampsia criteria, with maternal hypertension in preeclampsia (Kulkarni sample sizes, detective methods, and so on. In the future, et al. 2011). Early research among patients with meta-analyses, especially cumulative meta-analyses, may

give a more determined perspective of underlying effects. Bashford MT, Hefler LA, Vertrees TW, Roa BB & Gregg AR 2001 Of all the limitations, small sample sizes encumber Angiotensinogen and endothelial nitric oxide synthase gene polymorphisms among Hispanic patients with pre-eclampsia. American researchers most regarding deeper statistical analyses Journal of Obstetrics and Gynecology 184 1345–1350. (doi:10.1067/ based on the principles of ratios of the amount of mob.2001.115048) parameters to the subject sizes. In summary, many Bauknecht H, Vecsei P, Endres H & Hettenbach A 1982 Urinary free 18-hydroxycorticosterone, plasma aldosterone, and urinary aldoster- promising findings were reported about the interactions one metabolites in normal pregnancy. American Journal of Obstetrics with genetic polymorphisms and RAAS alterations in and Gynecology 144 28–34. preeclampsia but remain to be replicated. 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Received in ﬁnal form 20 January 2013 Accepted 31 January 2013 Accepted Preprint published online 31 January 2013 Journal of Molecular Endocrinology