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The role of the renin–angiotensin system in the pathogenesis of preeclampsia – New insights into the renin–angiotensin system in preeclampsia
Medical Hypotheses 82 (2014) 362–367
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The role of the renin–angiotensin system in the pathogenesis of preeclampsia – New insights into the renin–angiotensin system in preeclampsia q H. Seki ⇑ Center for Maternal, Fetal and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama 350-8550, Japan
a r t i c l e
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Article history: Received 7 October 2013 Accepted 31 December 2013
a b s t r a c t The renin–angiotensin system (RAS) plays an important role in the pathogenesis of hypertension. However, the role of RAS in preeclampsia is largely unknown, because the plasma concentration of renin and angiotensin (AII) is lower in preeclampsia than in normal pregnancy, whereas its cardinal sign is hypertension. A pressor response to AII infusions can predict the onset of preeclampsia, resulting in involvement of RAS in the pathogenesis of preeclampsia. It has been reported that patients with preeclampsia exhibit angiotensin type I receptor agonistic autoantibody (AT1-AA), suggesting the involvement of RAS in the pathogenesis of this condition. The physiological action of AT1-AA can explain the various clinical symptoms of preeclampsia. However, the significance of circulatory RAS, including AT1-AA, in the pathogenesis of preeclampsia remains obscure. Since many reports state that circulating RAS is thought to be suppressed in preeclampsia it is difficult to explain the onset of hypertension in preeclampsia by circulating RAS. Therefore, I propose new insights into the role of RAS in preeclampsia to resolve the contradiction as above-mentioned. The recent discovery of tissue RAS, on which prorenin and its receptor act, suggests a promising new direction in understanding the role of RAS in the pathogenesis of preeclampsia. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction The incidence of preeclampsia is estimated to be 2–7% [1]. Preeclampsia has a significant effect on maternal morbidity and mortality rate in the acute and medium-to-long–term periods. It also affects the fetus, increasing perinatal mortality, prematurity, and fetal growth restriction. [1–4]. Hypertension is the most important clinical symptom in preeclampsia [1]. According to a former definition and classification of preeclampsia in Japan, hypertension, proteinuria, and edema were all equally important signs for the diagnosis of preeclampsia, which does not accurately reflect the pathology of this condition. As a result, in 2005, the Japan Society of Obstetrics and Gynecology revised the definition and classification of preeclampsia to identify hypertension as the cardinal sign, thus more accurately reflecting the pathology and to accord with the definition from western countries (Tables 1a and 1b). Moreover, the classification by onset time of hypertension and/or proteinuria was added. Many recent reports [1,5–8] state that a wide variety of diseases exist and their pathology differs depending on severity and onset time. The studies have reported differing pathologies between mild
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and severe cases of preeclampsia [6] as well as between the earlyonset and late-onset types [7]. In addition, in some cases, hypertension develops first and leads to preeclampsia, whereas in other cases of preeclampsia, proteinuria is the initial symptom [8]. Furthermore, in one of the types of preeclampsia, maternal symptoms (hypertension and proteinuria) occur first, whereas in another, fetal symptoms (intrauterine growth retardation, oligohydramnios, etc.) are noted first. Thus, the pathology of preeclampsia is extremely diverse. Various etiologies and pathogenesis have been formulated or suggested for preeclampsia. With general acceptance of the ‘‘two-stage disorder’’ theory [9], it has become apparent that anti-angiogenesis factors play an important role in pathogenesis. [10–14] On the other hand, RAS is known to play an important role in the pathology of hypertension [15], but its involvement in the etiology and pathogenesis of preeclampsia remains obscure. In the early 1970s Gant et al. [16] performed experiments in which they infused angiotensin II (AII) into pregnant women and found that pregnant women with high susceptibility to AII had a high risk of developing preeclampsia, and that the occurrence of this complication was attributed to RAS. However, circulatory RAS in preeclampsia was suppressed compared with that in normal pregnancy [17–19]. Thus, the exact mechanisms involved in the pathogenesis of preeclampsia remain unknown. Various reports suggesting the involvement of RAS in the pathogenesis of preeclampsia [20–28] followed the discovery of
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Table 1a Definition and classification of pregnancy-induced hypertension by the Japanese Society of Obstetrics and Gynecology. 1. Name 2. Definition
3. Classification of disease types
The pathology previously termed ‘‘preeclampsia’’ is renamed as ‘‘pregnancy-induced hypertension (PIH)’’ This refers to cases in which hypertension is observed from the 20th week of pregnancy until 12 weeks after delivery or cases in which hypertension is accompanied by proteinuria, where both of these symptoms are not simply because of accidental complications of pregnancy Preeclampsia: This refers to cases in which hypertension develops and is accompanied by proteinuria after the 20th week of pregnancy and recovers to normal by 12 weeks after delivery Gestational hypertension: This refers to cases in which hypertension develops after the 20th week of pregnancy and recovers to normal by 12 weeks after delivery Superimposed preeclampsia: This refers to: (a) Cases in which chronic hypertension exists before the 20th week of pregnancy and is accompanied by proteinuria after the 20th week of pregnancy (b) Cases in which chronic hypertension and proteinuria exist before the 20th week of pregnancy and either or both of the symptoms become exacerbated after the 20th week of pregnancy (c) Cases in which renal disease presenting with only proteinuria exists before the 20th week of pregnancy and hypertension develops after the 20th week of pregnancy Eclampsia: This refers to cases in which convulsive seizure occurs before the 20th week of pregnancy, and epilepsy and secondary convulsion are eliminated. It is termed eclampsia of pregnancy, intrapartum eclampsia, or puerperal eclampsia depending on the period when convulsive seizure occurs
Table 1b Sub-classification by symptoms. The disease types are classified into mild and severe symptoms according to the degree of hypertension and proteinuria Mild symptoms
Severe symptoms
Classification of disease types by the timing of onset
1. Blood pressure (if any of the following is applicable):Systolic blood pressure is 140 mmHg or higher, but lower than 160 mmHgDiastolic pressure is 90 mmHg or higher, but lower than 110 mmHg 2. Proteinuria: P300 mg/day, <2 g/day 1. Blood pressure (if any of the following is applicable):Systolic blood pressure is 160 mmHg or higherDiastolic blood pressure is 110 mmHg or higher 2. Proteinuria: Proteinuria should be considered severe when the urine protein level is 2 g/day or higher. The judgment of the severity of proteinuria should be based, in principle, on the 24-h urine collections because a semiquantitative determination of urine protein level from a dipstick test of spot urine is poorly correlated with the quantitative method of using 24-h urine collection specimens. When only results from a dipstick test of spot urine can be obtained, proteinuria should be considered severe when consecutively judged positive with a score of 3 + or higher (300 mg/dL or higher) by using fresh urine specimens collected multiple times Preeclampsia that develops before and after the 32nd week of pregnancy is defined as the early-onset type (EO) and late-onset type (LO), respectively
expression of AT1-AA by Wallukat et al. [20] in a study that included patients with preeclampsia. Here, we summarize the current research findings relating to RAS in preeclampsia and investigate present problems and future prospects in this area of research.
Hypothesis: does RAS play an important role in developing preeclampsia? 1. ‘‘Two-stage disorder’’ theory Early in normal pregnancy, extravillous cytotrophoblasts of fetal origin invade the uterine spiral arteries of the decidua and myometrium. These invasive cytotrophoblasts replace the endothelial layer of the maternal spiral arteries, transforming them from narrow-caliber high-resistance vessels to wide-caliber low-resistance vessels capable of providing adequate placental perfusion to sustain the growing fetus, i.e., spiral artery remodeling [11,29]. If this remodeling of spiral artery does not occur correctly it results in preeclampsia [30]. Uterine natural killer cells (uNK) and regulatory T cells are thought to be important in modulating immune tolerance required for normal placental development as well as the induction of angiogenic factors and vascular remodeling [31,32]. In preeclampsia, maternal–fetal immunogenic maladaptation may occur, involving abnormal movement of essential uNK [30] and regulatory T cells [32,33] for pregnancy maintenance. The incorrect spiral artery remodeling in preeclampsia is mediated
by vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) [11]. Influx from maternal blood vessels to villous cavity typically begins to occur at 10–12 weeks after implantation, therefore, oxygen partial pressure is increased. However, because the remodeling of the spiral artery is incomplete in preeclampsia, the oxygen partial pressure is not increased in fetal placental circulation, resulting in a low oxygen state. Placental hypoxia stimulates the production of soluble fms-like tyrosine kinase-1 (sFlt-1) in trophoblast cells [10,34] and suppresses the production of PlGF [35]. sFlt-1 is the soluble receptor of VEGF, and PlGF is an sFlt-1 ligand belonging to the VEGF family. VEGF is thought to have an important role adequate placental perfusion through both angiogenesis and vasodilation. Therefore, overproduction of sFlt-1 and low PIGF levels in preeclampsia, reduce free VEGF and suppress angiogenesis in the placenta and prevents adequate placental perfusion. This results in a vicious cycle of low oxygen saturation in the placental circulation beginning during early pregnancy. The first stage of the ‘‘two-stage disorder’’ theory is the condition of hypoxemia of placental circulation described above. In the second stage of the ‘‘two-stage disorder’’ theory, the clinical symptoms of preeclampsia develop due to anti-angiogenic factors, which are the so-called ‘‘toxins of preeclampsia’’. In the second stage, anti-angiogenic factors such sFlt-1 and sEng cross the placenta and circulate in the maternal circulation system. In preeclampsia, plasma concentration of sFlt-1 [12,36] and sEng [13,14] are elevated but PlGF [37] is low in preeclamptic women. Elevated levels of anti-angiogenic factors in the maternal circulation impair endothelial cell function causing attenuated
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production of endothelial derived relaxing factors such as NO and prostacyclin, resulting in vasoconstriction and subsequent hypertension. In parallel, circulatory dysfunction of kidney occurs, resulting in proteinuria. In normal pregnancy RAS components such as AII, angiotensinconverting enzyme (ACE), and AT1 play an important role in decidualization and spiral artery remodeling [38]. In addition, there are published reports showing that prorenin, renin–protrenin receptor [(P)RR], and AT1 regulate placental angiogenesis through the VEGF expression [39,40]. Studies have found that RAS is altered in preeclampsia but the detailed mechanism and its role in the ‘‘twostage disorder’’ theory of preeclampsia remain unclear. Therefore, my perspective on this will be discussed below. 2. Literature review about the role of RAS in pathophysiology of preeclampsia and the points at issue Studies have found that circulatory RAS in preeclampsia is suppressed compared to that in normal pregnancy [17–19]. but it is unclear how suppressed circulatory RAS leads to hypertension in preeclampsia. The physiological action of AT1-AA is a very convenient to explain the pathophysiology in which vasoconstriction and hypercoagulability exist. The physiological functions of AT1AA are as follows: (i) to increase the production of sFlt-1 [21], (ii) to reduce fibrinolysis and increase PAI-1, to control the breakdown of extracellular matrix, and to control trophoblastic invasion [22], (iii) to control the breakdown of fibrinolysis and extracellular matrix in the kidney along with the increased production of PAI-1, and to aggravate proteinuria and renal function decline [23,24], (iv) to activate NADPH oxidase and to produce reactive oxygen species (ROS) [25]. (v) to deliver oxidative stress to placental tissue via ROS and disabling the function [26], (vi) to increase concentration of intracellular calcium [41,42], and (vii) to increase production of tissue factor, resulting in an increase of coagulation [27]. This can explain all clinical symptoms and placental pathologic changes seen in preeclampsia. In addition, AT1-AA is not found in normal pregnancy and non-pregnant hypertensive patients. This antibody is found only in preeclampsia, therefore it is thought to play a role in pathogenesis. However, it is difficult to explain the various pathologies of preeclampsia from the viewpoint of circulating factors, such as AT1AA, renin, and AII, alone. If preeclampsia develops by circulating factors alone, clinical symptoms should appear almost simultaneously in both the maternal and fetoplacental circulations and show a single pathophysiology. In some cases, hypertension develops first and leads to preeclampsia, whereas in other cases of preeclampsia, proteinuria is the initial symptom. Furthermore, in one type of preeclampsia, maternal symptoms (hypertension and proteinuria) occur first, whereas in another, fetal symptoms (intrauterine growth retardation, oligohydramnios, etc.) are noted first. As above-mentioned, the pathology of preeclampsia is extremely diverse. Therefore, it is difficult to explain the various pathologies of preeclampsia by circulating factors alone. AT1-AA acts by binding to its receptor, AT1. AT1 signaling does not only regulate most placental genes, but it is also implicated in the regulation of protein expression related to trophoblast invasion and angiogenesis [28]. Even in the presence of a high concentration of AT1-AA in plasma, AT1-AA can not act upon the tissues that do not express AT1. In order to clarify the significance of AT1-AA in the pathogenesis of preeclampsia, it is also important to analyze not only AT1-AA but also the expression site of AT1 as well as the amount and duration of expression. Several reports exist concerning the localization of the expression of AT1 in normal pregnancy [38,43,44]. Anton et al. investigated the AT1 and AT2 gene expression levels in the placental bed and found that its levels were reduced in pregnancy compared
to non-pregnant women, however no difference was observed between normal pregnancy and preeclampsia [45]. Herse et al. found that the level of AT1 gene expression in the decidua in preeclampsia was 5 times than that in normal pregnancy. Expression levels of renin, ACE, and angiotensinogen gene in the decidua were significantly higher compared to that in the placenta. In contrast, the expression level of the AT1 gene was significantly higher in the placenta. These results were consistent in both normal pregnancy and preeclampsia [46]. These findings indicate that the source of RAS components is maternal, whereas placenta is the action site. However, the pathogenesis of preeclampsia could not be explained by the amount and expression site of AT1, because there is no difference in the amount and expression site of AT1 between normal pregnancy and preeclampsia. Abdalla et al. conducted an interesting study of AT1 from a different point of view [47]. They reported that AT1 was present as a monomer in normal pregnancy, however, AT1 formed a heterodimer with the bradykinin B2 in preeclampsia. A negative feedback to oxidant stress was maintained in AT1 monomer, however, it was not maintained in AT1-B2 heterodimer. Enhanced AII sensitivity arising from the different isoforms of AT1 present in preeclampsia compared to normal pregnancy might be a factor in pathogenesis of preeclampsia [47]. This is the first report on receptor differences between normal pregnancy and preeclampsia (Fig. 1), although the reason for the mechanism of negative feedback and the presence of the heterodimer in preeclampsia is still unclear. From the studies discussed above, it is apparent that RAS may have important roles in both normal pregnancy and the pathogenesis of preeclampsia. Pringle et al. reported that prorenin, (pro)renin receptor and AT1 mRNA level correlated with VEGF expression [39]. Herr et al. reported that the potential capacity of angiotensin II influenced angiogenesis by the regulation of angiogenesis-associated genes via AT1 in human umbilical vein endothelial cells [40]. These studies suggested that RAS may contribute to the pathogenesis of preeclampsia by modulating production of angiogenic factors through AT1. Evidence is now emerging that the angiogenic system and RAS are not distinct, but may in fact co-operate to regulate expression of angiogenic genes and production of growth factors. RAS might play important roles in two-stage disorder theory of preeclampsia. 3. Future issues In the last five years, it has become clear that women with preeclampsia have a high risk of developing cardiovascular disorders in middle age [48,49]. AT1-AA is proposed as a risk factor in such cases [48]. RAS is also thought to be involved in preeclampsia, which has long lasting after effects on the health of women. Although there are numerous publications regarding the role of RAS in the etiology and pathogenesis of preeclampsia, circulatory RAS is suppressed in this disease. Therefore, the significance of circulatory RAS remains unclear in detail. Therefore, I propose that tissue RAS, whose physiological action can explain the etiology and pathogenesis of preeclampsia, rather than circulatory RAS, is important in the etiology and pathogenesis of preeclampsia and can resolve these problems. In 2002, Nguyen et al. discovered prorenin receptor [(P)RR] [50]. When prorenin is combined with (P)RR, the non-active prorenin enzyme achieves renin enzyme activity through the non-proteolytic pathway [51,52] (Fig. 2). Stimulation of (P)RR also activates AII and independent intracellular signal transduction [51–54]. This shows that (P)RR stimulates (P)RR unique signal transduction through the activation of prorenin, suggesting its involvement in the onset and progression of organ failure in diabetes [51–54]. This factor is able to stimulate (P)RR and to activate tissue RAS, despite
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Fig. 1. Morphology of angiotensin II type1 receptor in preeclampsia. In normal pregnancy, AT1 is present in monomer form. In preeclampsia, however, AT1 forms a heterodimer with the B2 bradykinin receptor. Reactive oxygen species (ROS) suppress the function of AT1 monomers but have no effect on AT1 that forms a heterodimer with the B2 bradykinin receptor (AT1-B2). AT1-B2 heterodimerization renders the AT1 resistant to inactivation by ROS. This resistance of AT1-B2 heterodimers to inactivation maintains AII signaling in preeclampsia, whereas inactivation of AT1 monomer by oxidant stress correlates with blunted AII signaling in normal pregnancy.
Fig. 2. Prorenin and prorenin receptor. When prorenin is combined with the prorenin receptor, structural change occurs in the prosegment (non-proteolytic pathway). The non-active prorenin enzyme gains renin enzyme activity through a non-proteolytic pathway. In addition, stimulation of prorenin receptor activates AII-independent intracellular signal transduction.
low circulating renin concentration, if prorenin remains high. Circulatory RAS in preeclampsia is thought to be suppressed because of low concentration of plasma renin [17,19] but tissue RAS may be activated in preeclampsia if plasma prorenin is high. Thus in tissue,
the most important factors in the RAS is not renin, but prorenin and the prorenin receptor. It is currently known that type 1 diabetes patients with high plasma prorenin in early pregnancy have a higher risk of
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developing preeclampsia. [55] The higher concentration of prorenin in the umbilical vein compared with the umbilical artery [56] indicates that prorenin is produced by trophoblasts. [57] Further, the female reproductive organ is the production source of prorenin. It is chiefly present in maternal tissue [58], ovarian follicular fluid [59–62], amnotic fluid [63], amnion, villus, villous plane, and placenta [64]. Uteroplacental renin and prorenin are reported to be involved in growth and differentiation during fetal development and in the maintenance of attenuation of placental vascular resistance during angiogenesis [65,66]. In addition, the concentration of prorenin in placental tissue of preeclampsia is reported to be significantly high [57]. Other studies, however, state the converse [67] or report no difference compared with that in normal pregnancy [68,69]. Prorenin is 40–50 times more abundant than renin in the plasma of diabetes patients [70]. In a rat model of type 1 diabetes, increased production of prorenin is implicated as a cause of increased blood pressure and organ failure [71]. Even in normal pregnancy, prorenin is also reported to be higher than rennin [72], suggesting a similarity of pathology with type 1 diabetes. Moreover, Singh et al. reported that the concentration of prorenin in placental tissue is significantly high [57]. Watababe et al. show that high circulating levels of soluble (P)PR during early pregnancy predicted a subsequent elevation in BP, and high concentration at delivery were significantly associated with preeclampsia [73]. Therefore, tissue RAS such as prorenin, (P)PR may play a role in pathogenesis of preeclampsia. To investigate the significance of tissue RAS, such as prorenin and prorenin receptor in the pathogenesis of preeclampsia, further studies are needed. Conclusion The ‘‘two-stage disorder’’ theory has been proposed to link the etiology and pathogenesis of preeclampsia. It is well understood that anti-angiogenesis factors play an important role in the development of preeclampsia. It is now emerging that in addition, tissue RAS may also play a significant role in the pathogenesis of preeclampsia. Future directions for research include establishment of a method for the measurement and collection of prorenin and (P)RR data in preeclampsia. Conflict of interest I hereby declare that I do not have any conflicts of interest to declare. References [1] Sibai BM, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99. [2] Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DI. Pre-eclampsia is associated with increased with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke 2009;40:1176–80. [3] Bauer ST, Cleary KL. Cardiopulmonary complications of pre-eclampsia. Semin Perinatol 2009;33:158–65. [4] Zeeman GG. Neurologic complications of pre-eclampsia. Semin Perinatol 2009;33:166–72. [5] Vatten LJ, Skaerven R. Is pre-eclampsia more than one disease? BJOG 2004;111:298–302. [6] Satoh K, Seki H, Sakamoto H. Role of prostaglandins in pregnancy-induced hypertension. Am J Kidney Dis 1991;17:133–8. [7] Rolfo A, Many A, Racano A, et al. Abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies. PLoS One 2010;5:e13288. [8] Stettler RW, Cunningham FG. Natural history of chronic proteinuria complicating pregnancy. Am J Obstet Gynecol 1992;167:1219–24. [9] Roberts JM. Preeclampsia: what we know and what we do not know. Semin Perinatol 2000;24:24–8. [10] Karamanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the ‘‘chickenand-egg’’ question. Endocrinology 2004;145:4835–7. [11] Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology 2009;24:147–58.
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The role of the renin–angiotensin system in the pathogenesis of preeclampsia – New insights into the renin–angiotensin system in preeclampsia q H. Seki ⇑ Center for Maternal, Fetal and Neonatal Medicine, Saitama Medical Center, Saitama Medical University, 1981, Kamoda, Kawagoe, Saitama 350-8550, Japan
a r t i c l e
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Article history: Received 7 October 2013 Accepted 31 December 2013
a b s t r a c t The renin–angiotensin system (RAS) plays an important role in the pathogenesis of hypertension. However, the role of RAS in preeclampsia is largely unknown, because the plasma concentration of renin and angiotensin (AII) is lower in preeclampsia than in normal pregnancy, whereas its cardinal sign is hypertension. A pressor response to AII infusions can predict the onset of preeclampsia, resulting in involvement of RAS in the pathogenesis of preeclampsia. It has been reported that patients with preeclampsia exhibit angiotensin type I receptor agonistic autoantibody (AT1-AA), suggesting the involvement of RAS in the pathogenesis of this condition. The physiological action of AT1-AA can explain the various clinical symptoms of preeclampsia. However, the significance of circulatory RAS, including AT1-AA, in the pathogenesis of preeclampsia remains obscure. Since many reports state that circulating RAS is thought to be suppressed in preeclampsia it is difficult to explain the onset of hypertension in preeclampsia by circulating RAS. Therefore, I propose new insights into the role of RAS in preeclampsia to resolve the contradiction as above-mentioned. The recent discovery of tissue RAS, on which prorenin and its receptor act, suggests a promising new direction in understanding the role of RAS in the pathogenesis of preeclampsia. Ó 2014 Elsevier Ltd. All rights reserved.
Introduction The incidence of preeclampsia is estimated to be 2–7% [1]. Preeclampsia has a significant effect on maternal morbidity and mortality rate in the acute and medium-to-long–term periods. It also affects the fetus, increasing perinatal mortality, prematurity, and fetal growth restriction. [1–4]. Hypertension is the most important clinical symptom in preeclampsia [1]. According to a former definition and classification of preeclampsia in Japan, hypertension, proteinuria, and edema were all equally important signs for the diagnosis of preeclampsia, which does not accurately reflect the pathology of this condition. As a result, in 2005, the Japan Society of Obstetrics and Gynecology revised the definition and classification of preeclampsia to identify hypertension as the cardinal sign, thus more accurately reflecting the pathology and to accord with the definition from western countries (Tables 1a and 1b). Moreover, the classification by onset time of hypertension and/or proteinuria was added. Many recent reports [1,5–8] state that a wide variety of diseases exist and their pathology differs depending on severity and onset time. The studies have reported differing pathologies between mild
q
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and severe cases of preeclampsia [6] as well as between the earlyonset and late-onset types [7]. In addition, in some cases, hypertension develops first and leads to preeclampsia, whereas in other cases of preeclampsia, proteinuria is the initial symptom [8]. Furthermore, in one of the types of preeclampsia, maternal symptoms (hypertension and proteinuria) occur first, whereas in another, fetal symptoms (intrauterine growth retardation, oligohydramnios, etc.) are noted first. Thus, the pathology of preeclampsia is extremely diverse. Various etiologies and pathogenesis have been formulated or suggested for preeclampsia. With general acceptance of the ‘‘two-stage disorder’’ theory [9], it has become apparent that anti-angiogenesis factors play an important role in pathogenesis. [10–14] On the other hand, RAS is known to play an important role in the pathology of hypertension [15], but its involvement in the etiology and pathogenesis of preeclampsia remains obscure. In the early 1970s Gant et al. [16] performed experiments in which they infused angiotensin II (AII) into pregnant women and found that pregnant women with high susceptibility to AII had a high risk of developing preeclampsia, and that the occurrence of this complication was attributed to RAS. However, circulatory RAS in preeclampsia was suppressed compared with that in normal pregnancy [17–19]. Thus, the exact mechanisms involved in the pathogenesis of preeclampsia remain unknown. Various reports suggesting the involvement of RAS in the pathogenesis of preeclampsia [20–28] followed the discovery of
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Table 1a Definition and classification of pregnancy-induced hypertension by the Japanese Society of Obstetrics and Gynecology. 1. Name 2. Definition
3. Classification of disease types
The pathology previously termed ‘‘preeclampsia’’ is renamed as ‘‘pregnancy-induced hypertension (PIH)’’ This refers to cases in which hypertension is observed from the 20th week of pregnancy until 12 weeks after delivery or cases in which hypertension is accompanied by proteinuria, where both of these symptoms are not simply because of accidental complications of pregnancy Preeclampsia: This refers to cases in which hypertension develops and is accompanied by proteinuria after the 20th week of pregnancy and recovers to normal by 12 weeks after delivery Gestational hypertension: This refers to cases in which hypertension develops after the 20th week of pregnancy and recovers to normal by 12 weeks after delivery Superimposed preeclampsia: This refers to: (a) Cases in which chronic hypertension exists before the 20th week of pregnancy and is accompanied by proteinuria after the 20th week of pregnancy (b) Cases in which chronic hypertension and proteinuria exist before the 20th week of pregnancy and either or both of the symptoms become exacerbated after the 20th week of pregnancy (c) Cases in which renal disease presenting with only proteinuria exists before the 20th week of pregnancy and hypertension develops after the 20th week of pregnancy Eclampsia: This refers to cases in which convulsive seizure occurs before the 20th week of pregnancy, and epilepsy and secondary convulsion are eliminated. It is termed eclampsia of pregnancy, intrapartum eclampsia, or puerperal eclampsia depending on the period when convulsive seizure occurs
Table 1b Sub-classification by symptoms. The disease types are classified into mild and severe symptoms according to the degree of hypertension and proteinuria Mild symptoms
Severe symptoms
Classification of disease types by the timing of onset
1. Blood pressure (if any of the following is applicable):Systolic blood pressure is 140 mmHg or higher, but lower than 160 mmHgDiastolic pressure is 90 mmHg or higher, but lower than 110 mmHg 2. Proteinuria: P300 mg/day, <2 g/day 1. Blood pressure (if any of the following is applicable):Systolic blood pressure is 160 mmHg or higherDiastolic blood pressure is 110 mmHg or higher 2. Proteinuria: Proteinuria should be considered severe when the urine protein level is 2 g/day or higher. The judgment of the severity of proteinuria should be based, in principle, on the 24-h urine collections because a semiquantitative determination of urine protein level from a dipstick test of spot urine is poorly correlated with the quantitative method of using 24-h urine collection specimens. When only results from a dipstick test of spot urine can be obtained, proteinuria should be considered severe when consecutively judged positive with a score of 3 + or higher (300 mg/dL or higher) by using fresh urine specimens collected multiple times Preeclampsia that develops before and after the 32nd week of pregnancy is defined as the early-onset type (EO) and late-onset type (LO), respectively
expression of AT1-AA by Wallukat et al. [20] in a study that included patients with preeclampsia. Here, we summarize the current research findings relating to RAS in preeclampsia and investigate present problems and future prospects in this area of research.
Hypothesis: does RAS play an important role in developing preeclampsia? 1. ‘‘Two-stage disorder’’ theory Early in normal pregnancy, extravillous cytotrophoblasts of fetal origin invade the uterine spiral arteries of the decidua and myometrium. These invasive cytotrophoblasts replace the endothelial layer of the maternal spiral arteries, transforming them from narrow-caliber high-resistance vessels to wide-caliber low-resistance vessels capable of providing adequate placental perfusion to sustain the growing fetus, i.e., spiral artery remodeling [11,29]. If this remodeling of spiral artery does not occur correctly it results in preeclampsia [30]. Uterine natural killer cells (uNK) and regulatory T cells are thought to be important in modulating immune tolerance required for normal placental development as well as the induction of angiogenic factors and vascular remodeling [31,32]. In preeclampsia, maternal–fetal immunogenic maladaptation may occur, involving abnormal movement of essential uNK [30] and regulatory T cells [32,33] for pregnancy maintenance. The incorrect spiral artery remodeling in preeclampsia is mediated
by vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) [11]. Influx from maternal blood vessels to villous cavity typically begins to occur at 10–12 weeks after implantation, therefore, oxygen partial pressure is increased. However, because the remodeling of the spiral artery is incomplete in preeclampsia, the oxygen partial pressure is not increased in fetal placental circulation, resulting in a low oxygen state. Placental hypoxia stimulates the production of soluble fms-like tyrosine kinase-1 (sFlt-1) in trophoblast cells [10,34] and suppresses the production of PlGF [35]. sFlt-1 is the soluble receptor of VEGF, and PlGF is an sFlt-1 ligand belonging to the VEGF family. VEGF is thought to have an important role adequate placental perfusion through both angiogenesis and vasodilation. Therefore, overproduction of sFlt-1 and low PIGF levels in preeclampsia, reduce free VEGF and suppress angiogenesis in the placenta and prevents adequate placental perfusion. This results in a vicious cycle of low oxygen saturation in the placental circulation beginning during early pregnancy. The first stage of the ‘‘two-stage disorder’’ theory is the condition of hypoxemia of placental circulation described above. In the second stage of the ‘‘two-stage disorder’’ theory, the clinical symptoms of preeclampsia develop due to anti-angiogenic factors, which are the so-called ‘‘toxins of preeclampsia’’. In the second stage, anti-angiogenic factors such sFlt-1 and sEng cross the placenta and circulate in the maternal circulation system. In preeclampsia, plasma concentration of sFlt-1 [12,36] and sEng [13,14] are elevated but PlGF [37] is low in preeclamptic women. Elevated levels of anti-angiogenic factors in the maternal circulation impair endothelial cell function causing attenuated
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production of endothelial derived relaxing factors such as NO and prostacyclin, resulting in vasoconstriction and subsequent hypertension. In parallel, circulatory dysfunction of kidney occurs, resulting in proteinuria. In normal pregnancy RAS components such as AII, angiotensinconverting enzyme (ACE), and AT1 play an important role in decidualization and spiral artery remodeling [38]. In addition, there are published reports showing that prorenin, renin–protrenin receptor [(P)RR], and AT1 regulate placental angiogenesis through the VEGF expression [39,40]. Studies have found that RAS is altered in preeclampsia but the detailed mechanism and its role in the ‘‘twostage disorder’’ theory of preeclampsia remain unclear. Therefore, my perspective on this will be discussed below. 2. Literature review about the role of RAS in pathophysiology of preeclampsia and the points at issue Studies have found that circulatory RAS in preeclampsia is suppressed compared to that in normal pregnancy [17–19]. but it is unclear how suppressed circulatory RAS leads to hypertension in preeclampsia. The physiological action of AT1-AA is a very convenient to explain the pathophysiology in which vasoconstriction and hypercoagulability exist. The physiological functions of AT1AA are as follows: (i) to increase the production of sFlt-1 [21], (ii) to reduce fibrinolysis and increase PAI-1, to control the breakdown of extracellular matrix, and to control trophoblastic invasion [22], (iii) to control the breakdown of fibrinolysis and extracellular matrix in the kidney along with the increased production of PAI-1, and to aggravate proteinuria and renal function decline [23,24], (iv) to activate NADPH oxidase and to produce reactive oxygen species (ROS) [25]. (v) to deliver oxidative stress to placental tissue via ROS and disabling the function [26], (vi) to increase concentration of intracellular calcium [41,42], and (vii) to increase production of tissue factor, resulting in an increase of coagulation [27]. This can explain all clinical symptoms and placental pathologic changes seen in preeclampsia. In addition, AT1-AA is not found in normal pregnancy and non-pregnant hypertensive patients. This antibody is found only in preeclampsia, therefore it is thought to play a role in pathogenesis. However, it is difficult to explain the various pathologies of preeclampsia from the viewpoint of circulating factors, such as AT1AA, renin, and AII, alone. If preeclampsia develops by circulating factors alone, clinical symptoms should appear almost simultaneously in both the maternal and fetoplacental circulations and show a single pathophysiology. In some cases, hypertension develops first and leads to preeclampsia, whereas in other cases of preeclampsia, proteinuria is the initial symptom. Furthermore, in one type of preeclampsia, maternal symptoms (hypertension and proteinuria) occur first, whereas in another, fetal symptoms (intrauterine growth retardation, oligohydramnios, etc.) are noted first. As above-mentioned, the pathology of preeclampsia is extremely diverse. Therefore, it is difficult to explain the various pathologies of preeclampsia by circulating factors alone. AT1-AA acts by binding to its receptor, AT1. AT1 signaling does not only regulate most placental genes, but it is also implicated in the regulation of protein expression related to trophoblast invasion and angiogenesis [28]. Even in the presence of a high concentration of AT1-AA in plasma, AT1-AA can not act upon the tissues that do not express AT1. In order to clarify the significance of AT1-AA in the pathogenesis of preeclampsia, it is also important to analyze not only AT1-AA but also the expression site of AT1 as well as the amount and duration of expression. Several reports exist concerning the localization of the expression of AT1 in normal pregnancy [38,43,44]. Anton et al. investigated the AT1 and AT2 gene expression levels in the placental bed and found that its levels were reduced in pregnancy compared
to non-pregnant women, however no difference was observed between normal pregnancy and preeclampsia [45]. Herse et al. found that the level of AT1 gene expression in the decidua in preeclampsia was 5 times than that in normal pregnancy. Expression levels of renin, ACE, and angiotensinogen gene in the decidua were significantly higher compared to that in the placenta. In contrast, the expression level of the AT1 gene was significantly higher in the placenta. These results were consistent in both normal pregnancy and preeclampsia [46]. These findings indicate that the source of RAS components is maternal, whereas placenta is the action site. However, the pathogenesis of preeclampsia could not be explained by the amount and expression site of AT1, because there is no difference in the amount and expression site of AT1 between normal pregnancy and preeclampsia. Abdalla et al. conducted an interesting study of AT1 from a different point of view [47]. They reported that AT1 was present as a monomer in normal pregnancy, however, AT1 formed a heterodimer with the bradykinin B2 in preeclampsia. A negative feedback to oxidant stress was maintained in AT1 monomer, however, it was not maintained in AT1-B2 heterodimer. Enhanced AII sensitivity arising from the different isoforms of AT1 present in preeclampsia compared to normal pregnancy might be a factor in pathogenesis of preeclampsia [47]. This is the first report on receptor differences between normal pregnancy and preeclampsia (Fig. 1), although the reason for the mechanism of negative feedback and the presence of the heterodimer in preeclampsia is still unclear. From the studies discussed above, it is apparent that RAS may have important roles in both normal pregnancy and the pathogenesis of preeclampsia. Pringle et al. reported that prorenin, (pro)renin receptor and AT1 mRNA level correlated with VEGF expression [39]. Herr et al. reported that the potential capacity of angiotensin II influenced angiogenesis by the regulation of angiogenesis-associated genes via AT1 in human umbilical vein endothelial cells [40]. These studies suggested that RAS may contribute to the pathogenesis of preeclampsia by modulating production of angiogenic factors through AT1. Evidence is now emerging that the angiogenic system and RAS are not distinct, but may in fact co-operate to regulate expression of angiogenic genes and production of growth factors. RAS might play important roles in two-stage disorder theory of preeclampsia. 3. Future issues In the last five years, it has become clear that women with preeclampsia have a high risk of developing cardiovascular disorders in middle age [48,49]. AT1-AA is proposed as a risk factor in such cases [48]. RAS is also thought to be involved in preeclampsia, which has long lasting after effects on the health of women. Although there are numerous publications regarding the role of RAS in the etiology and pathogenesis of preeclampsia, circulatory RAS is suppressed in this disease. Therefore, the significance of circulatory RAS remains unclear in detail. Therefore, I propose that tissue RAS, whose physiological action can explain the etiology and pathogenesis of preeclampsia, rather than circulatory RAS, is important in the etiology and pathogenesis of preeclampsia and can resolve these problems. In 2002, Nguyen et al. discovered prorenin receptor [(P)RR] [50]. When prorenin is combined with (P)RR, the non-active prorenin enzyme achieves renin enzyme activity through the non-proteolytic pathway [51,52] (Fig. 2). Stimulation of (P)RR also activates AII and independent intracellular signal transduction [51–54]. This shows that (P)RR stimulates (P)RR unique signal transduction through the activation of prorenin, suggesting its involvement in the onset and progression of organ failure in diabetes [51–54]. This factor is able to stimulate (P)RR and to activate tissue RAS, despite
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Fig. 1. Morphology of angiotensin II type1 receptor in preeclampsia. In normal pregnancy, AT1 is present in monomer form. In preeclampsia, however, AT1 forms a heterodimer with the B2 bradykinin receptor. Reactive oxygen species (ROS) suppress the function of AT1 monomers but have no effect on AT1 that forms a heterodimer with the B2 bradykinin receptor (AT1-B2). AT1-B2 heterodimerization renders the AT1 resistant to inactivation by ROS. This resistance of AT1-B2 heterodimers to inactivation maintains AII signaling in preeclampsia, whereas inactivation of AT1 monomer by oxidant stress correlates with blunted AII signaling in normal pregnancy.
Fig. 2. Prorenin and prorenin receptor. When prorenin is combined with the prorenin receptor, structural change occurs in the prosegment (non-proteolytic pathway). The non-active prorenin enzyme gains renin enzyme activity through a non-proteolytic pathway. In addition, stimulation of prorenin receptor activates AII-independent intracellular signal transduction.
low circulating renin concentration, if prorenin remains high. Circulatory RAS in preeclampsia is thought to be suppressed because of low concentration of plasma renin [17,19] but tissue RAS may be activated in preeclampsia if plasma prorenin is high. Thus in tissue,
the most important factors in the RAS is not renin, but prorenin and the prorenin receptor. It is currently known that type 1 diabetes patients with high plasma prorenin in early pregnancy have a higher risk of
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developing preeclampsia. [55] The higher concentration of prorenin in the umbilical vein compared with the umbilical artery [56] indicates that prorenin is produced by trophoblasts. [57] Further, the female reproductive organ is the production source of prorenin. It is chiefly present in maternal tissue [58], ovarian follicular fluid [59–62], amnotic fluid [63], amnion, villus, villous plane, and placenta [64]. Uteroplacental renin and prorenin are reported to be involved in growth and differentiation during fetal development and in the maintenance of attenuation of placental vascular resistance during angiogenesis [65,66]. In addition, the concentration of prorenin in placental tissue of preeclampsia is reported to be significantly high [57]. Other studies, however, state the converse [67] or report no difference compared with that in normal pregnancy [68,69]. Prorenin is 40–50 times more abundant than renin in the plasma of diabetes patients [70]. In a rat model of type 1 diabetes, increased production of prorenin is implicated as a cause of increased blood pressure and organ failure [71]. Even in normal pregnancy, prorenin is also reported to be higher than rennin [72], suggesting a similarity of pathology with type 1 diabetes. Moreover, Singh et al. reported that the concentration of prorenin in placental tissue is significantly high [57]. Watababe et al. show that high circulating levels of soluble (P)PR during early pregnancy predicted a subsequent elevation in BP, and high concentration at delivery were significantly associated with preeclampsia [73]. Therefore, tissue RAS such as prorenin, (P)PR may play a role in pathogenesis of preeclampsia. To investigate the significance of tissue RAS, such as prorenin and prorenin receptor in the pathogenesis of preeclampsia, further studies are needed. Conclusion The ‘‘two-stage disorder’’ theory has been proposed to link the etiology and pathogenesis of preeclampsia. It is well understood that anti-angiogenesis factors play an important role in the development of preeclampsia. It is now emerging that in addition, tissue RAS may also play a significant role in the pathogenesis of preeclampsia. Future directions for research include establishment of a method for the measurement and collection of prorenin and (P)RR data in preeclampsia. Conflict of interest I hereby declare that I do not have any conflicts of interest to declare. References [1] Sibai BM, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99. [2] Kajantie E, Eriksson JG, Osmond C, Thornburg K, Barker DI. Pre-eclampsia is associated with increased with increased risk of stroke in the adult offspring: the Helsinki birth cohort study. Stroke 2009;40:1176–80. [3] Bauer ST, Cleary KL. Cardiopulmonary complications of pre-eclampsia. Semin Perinatol 2009;33:158–65. [4] Zeeman GG. Neurologic complications of pre-eclampsia. Semin Perinatol 2009;33:166–72. [5] Vatten LJ, Skaerven R. Is pre-eclampsia more than one disease? BJOG 2004;111:298–302. [6] Satoh K, Seki H, Sakamoto H. Role of prostaglandins in pregnancy-induced hypertension. Am J Kidney Dis 1991;17:133–8. [7] Rolfo A, Many A, Racano A, et al. Abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies. PLoS One 2010;5:e13288. [8] Stettler RW, Cunningham FG. Natural history of chronic proteinuria complicating pregnancy. Am J Obstet Gynecol 1992;167:1219–24. [9] Roberts JM. Preeclampsia: what we know and what we do not know. Semin Perinatol 2000;24:24–8. [10] Karamanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the ‘‘chickenand-egg’’ question. Endocrinology 2004;145:4835–7. [11] Wang A, Rana S, Karumanchi SA. Preeclampsia: the role of angiogenic factors in its pathogenesis. Physiology 2009;24:147–58.
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