Review: Sex specific programming: A critical role for the renal renin–angiotensin system

Article Outline

• Abstract
• 1. Developmental programming
  • 1.1. Animal models of programming
  • 1.2. Sex differences in the programming of disease
  • 1.3. Nephron endowment: a key contributor to developmental programming
• 2. The renin–angiotensin system
  • 2.1. The role of the RAS in development
  • 2.2. Sex differences in the RAS
    • 2.2.1. Kidney
    • 2.2.2. Placenta
• 3. The role of the renal RAS in programming models
  • 3.1. Prenatal glucocorticoid exposure
  • 3.2. Uteroplacental insufficiency
  • 3.3. Maternal dietary manipulations
• 4. Conclusions
• Acknowledgements
• Conflict of interest
• References
• Copyright

Abstract 

The “Developmental Origins of Health and Disease” hypothesis has caused resurgence of interest in understanding the factors regulating fetal development. A multitude of prenatal perturbations may contribute to the onset of diseases in adulthood including cardiovascular and renal diseases. Using animal models such as maternal glucocorticoid exposure, maternal calorie or protein restriction and uteroplacental insufficiency, studies have identified alterations in kidney development as being a common feature. The formation of a low nephron endowment may result in impaired renal function and in turn may contribute to disease. An interesting feature in many animal models of developmental programming is the disparity between males and females in the timing of onset and severity of disease outcomes. The same prenatal insult does not always affect males and females in the same way or to the same degree. Recently, our studies have focused on changes induced in the kidney of both the fetus and the offspring, following a perturbation during pregnancy. We have shown that changes in the renin–angiotensin system (RAS) occur in the kidney. The changes are often sex specific which may in part explain the observed sex differences in disease outcomes and severity. This review explores the evidence suggesting a critical role for the RAS in sex specific developmental programming of disease with particular reference to the immediate and long term changes in the local RAS within the kidney.

Keywords: Developmental programming, Nephron number, Renin–angiotensin system, Sex differences

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1. Developmental programming 

The Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that individuals who experience a sub-optimal in utero environment are at an increased risk of developing adult onset diseases. This concept, developed over the last 20 years, is strongly supported by epidemiological and experimental evidence showing that offspring exposed to prenatal perturbations, particularly those born small, have an increased susceptibility to a myriad of diseases including cardiovascular, renal and metabolic disease [1], [2], [3]. In the human, there are many factors that may compromise development of the fetus including poor maternal diet, global food restriction, exposure to environmental toxins or stress, pre-existing maternal disease (such as diabetes or hypertension) and uteroplacental insufficiency (resulting in hypoxia and/or nutrient deficiencies). The DOHaD hypothesis suggests that the fetus responds to these conditions by making alterations to its own growth and metabolism to ensure immediate survival [4]. However, these adaptations result in long term alterations in the structure and function of various organs and ultimately may result in disease.

Research in the last decade has concentrated on how organs and systems are affected during development. This review shall focus on the compelling evidence that alterations in kidney development and permanent changes in the renal renin–angiotensin system (RAS) may provide a mechanistic link between a prenatal perturbation and disease in adulthood. We also examine the body of evidence suggesting a role for the renin–angiotensin system (RAS) in the development and function of the placenta. Finally, the significant sex differences in the RAS and the implications of these sex specific differences for developmental programming of disease are discussed.

1.1. Animal models of programming 

Experimental manipulation of the maternal, and thus prenatal environment, in animal models has given insights into the mechanisms contributing to the programming phenomenon [5]. Maternal undernutrition through restriction of calories, protein or specific vitamin intake has been widely used experimentally in sheep and rats and to a lesser degree, guinea pigs, mice and baboons. Models of placental insufficiency, which results in fetal nutrient restriction as well as fetal hypoxia have been developed in rats, via ligation of uterine blood vessels [6], [7] or injection of microspheres in the placental circulation of the sheep [8] Maternal glucocorticoid exposure has also been used extensively as a programming agent in rats [9] and sheep [10] to mimic natural elevations in stress hormones during pregnancy or to model the exposure to synthetic glucocorticoids a baby may receive if the mother threatens preterm delivery.

It should be noted that there is likely to be an overlap between these models. For example, maternal undernutrition can stimulate glucocorticoid production whilst excessive glucocorticoids over a number of days can decrease maternal food intake [11]. A challenge for researchers is to bring together data from a wide range of models in order to identify key mechanistic pathways. This is important as identification of altered development in a particular organ or system that occurs in a number of these models is likely to be of greater relevance to the human than a change that occurs only in a particular model or species. As discussed below, impaired kidney development, resulting in a reduced nephron endowment and the associated changes in the renal renin–angiotensin system (RAS) have been found in multiple models and species suggesting a critical role for this organ and system.

1.2. Sex differences in the programming of disease 

It has long been recognised that there are distinct differences in the onset and severity of disease in men and women. For example, hypertension is more common in men than age-matched pre-menopausal women but this susceptibility reverses after women reach menopause [12]. In animal models of programming, sex differences are also apparent with males most often affected more severely. Moderate protein restriction results in hypertension in male but not female offspring and it is only when the insult becomes more severe, that the female develops a hypertensive phenotype [13], [14]. A recent review on the sex differences in the programming of hypertension highlights that whilst the sex hormones undoubtedly play an important role, sex differences in other systems, most notably the RAS, are also strongly implicated [15], [16].

1.3. Nephron endowment: a key contributor to developmental programming 

Nephron number has been intrinsically linked to the development of hypertension [17] due to the crucial role of the kidneys in regulating sodium and fluid balance. Sodium excretion by the kidney is tightly regulated, with urinary sodium output precisely matched to dietary intake. Powerful renal mechanisms ensure that changes in sodium intake are matched by equivalent increases or decreases in renal sodium excretion. Thus the kidney plays a major role in the maintenance of an optimal internal fluid environment and the regulation of arterial pressure. It is widely accepted that sustained hypertension is not possible without an alteration of kidney function [17], [18]. In humans, low birth weight (a surrogate marker of a poor in utero environment), has been shown to correlate strongly with a reduced nephron endowment [19]. In addition, studies in the human provide evidence that a low nephron number correlates with elevated blood pressure. Keller et al. [20] showed that nephron number was significantly lower in people with demonstrated hypertension and a similar finding has recently been reported in adult indigenous Australians [21].

In many animal models of developmentally programmed hypertension (including maternal low protein diet, maternal glucocorticoid exposure and uteroplacental insufficiency) altered kidney development resulting in a permanent reduction in offspring nephron endowment has been observed [22]. The timing of the prenatal insult may be particularly important in mediating alterations in nephron endowment with the early stages of kidney development being particularly susceptible [22]. It is thus important to recognise that the period of nephrogenesis varies amongst species with the human and sheep completing nephron formation prior to birth whilst most rodents continue this process for a number of day after birth [22]. This means both the prenatal and postnatal environment can affect nephron endowment in the rodent.

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2. The renin–angiotensin system 

The renin–angiotensin system (RAS) is a systemic hormonal cascade which mediates sodium reabsorption, vasoconstriction, aldosterone production and vasopressin secretion. The substrate, angiotensinogen produced in the liver, is cleaved by renin (from the kidney) to produce the decapeptide, angiotensin I. After cleaving by angiotensin converting enzyme (ACE), the most biologically active peptide, angiotensin II is produced which acts on the angiotensin type 1 (AT1) or type-2 (AT2) receptors. In the rodent there are two subtypes of the AT1 receptor, AT1a and AT1b. Recently, novel actions of angiotensin II have been demonstrated including actions on insulin secretion [23] and sensitisation [24] and interest has focused on a second “arm” of the RAS which results in other angiotensin peptide fragments (for review see [25]). As shown in Fig. 1, this arm involves the production of angiotensin 1–9 or angiotensin 1–7 by ACE2 [26] from angiotensin I or angiotensin II respectively. Angiotensin 1–9 can then be converted to angiotensin 1–7 by ACE. Angiotensin 1–7 acts on the Mas proto-oncogene receptor as well as the AT2 receptor and has vasodilatory and anti-proliferative effects. This arm of the system is thus thought to counterbalance the effects of angiotensin II acting on the AT1 receptor (for review see [27]).

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• Fig. 1 

  A contemporary view of the renin–angiotensin system. Abbreviations: ACE=angiotensin converting enzyme, ACE-2=angiotensin converting enzyme-2, AT1=angiotensin receptor type 1, AT2=angiotensin receptor type-2, Ang 1–7=angiotensin 1–7, Ang 1–9=angiotensin 1–9, Mas-R=mas proto-oncogene receptor.

In addition to the circulating RAS, there exists in many organs, including the kidney and placenta, a local RAS, which acts in an autocrine/paracrine manner.

2.1. The role of the RAS in development 

The RAS plays a crucial role in the growth, development and functioning of many organs including the kidney and placenta. The developing kidney expresses all components of the RAS from early in renal development in the human [28], sheep [29] and rodent [30]. During renal organogenesis, angiotensin II acting on the AT1 receptor mediates growth and proliferation of renal tubules [31] and branching morphogenesis [32]. In contrast, the AT2 receptor in the fetal kidney has anti-proliferative actions in the renomedullary interstitial cells and acts to mediate apoptosis [33]. The function of the RAS in fetal life is quite different from that in the adult. Studies in fetal sheep have shown that infusion of angiotensin II causes a natriuresis and diuresis [34] and does not readily stimulate aldosterone production [35]. Thus, it is thought that angiotensin II has a major role in maintaining fetal fluid balance by ensuring a high urine production, thereby contributing to the production of amniotic fluid [36]. It is therefore not surprising that ACE inhibitors are not recommended for pregnant women as they can readily cross the placenta and result in anuria and oligohydramnios [37].

The uteroplacental circulation has a local RAS that plays important roles in placental angiogenesis and in modulating placental production of cytokines, growth factors and vasoactive substances, which also influence fetal development. AT1 receptor stimulation by angiotensin II has been shown to promote trophoblast invasion, angiogenesis, growth, branching morphogenesis and proliferation in the placenta and to regulate vasoconstriction in the uterine spiral arteries [38]. In the human AT1 receptors have been shown to be expressed in the chorionic villi, indicating a role of the RAS in controlling circulation of fetal blood within the placenta [39]. The role of the RAS in regulating placental blood flow has also been indicated in the rat, as maternal perturbations have been shown to alter placental expression of AT1 receptors [40] and in-vitro studies have demonstrated a role for the AT2 receptor in modifying vascular contraction [41].

2.2. Sex differences in the RAS 

It has become increasingly apparent that it is the balance between the vasopressor (ACE/AngII/AT₁R axis) and vasodepressor (Ang(1–7)/ACE2/AT₂R axis) arms which is important in regulating disease [25], [27]. It has been clearly demonstrated that sex hormones differentially regulate these pathways, with testosterone increasing expression of renin and the AT₁R and up-regulating the vasopressor arm of the RAS and estrogen increasing ACE2 and AT₂R and up-regulating the vasodepressor arm [42], [43].

Levels of AT1 and AT2 receptors have been shown to differ between sexes in rat kidneys with males having significantly lower expression of AT2 receptor mRNA in both normal [43] and spontaneously hypertensive rats [44]. Renal expression levels of the AT1b receptor are also higher in females [9], [43] whilst the AT1a receptor gene expression has been reported as similar [43] or elevated in females [9]. As yet, there is little information if these sex differences in receptor levels are present during development. One study in sheep has shown female fetuses have more AT2 receptor than male fetuses at mid gestation whilst males had more AT1 receptor in late gestation [45].

There is little published information on sex differences in the placental RAS. We have recently explored the differences that exist in the placental RAS between males and females in the rabbit, which, similar to humans, has a haemochorial discoid placenta [46]. The developing embryo implants on day 7 and gestation is 32 days in length. In the rabbit fetal sex had no effect on the level of placental renin, AT₁R or AT₂R at 28 days of gestation (Fig. 2). In the rabbit, the expression level of AT₂R is also high in placental tissue, with the ratio of AT₂R to AT₁R expression being close to 1, whereas renal tissue AT₁R exceeds AT₂R mRNA expression in non-pregnant rabbits. Most studies in rodents have yet to examine placentae from male and female fetuses separately. This is an important area for future research as it likely that differences within the placental RAS also exist which may influence growth and development.

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• Fig. 2 

  Placental renin, AT1 and AT2 receptor mRNA expression in rabbit placenta from male or female offspring at day 28 of a 32 day gestation from normotensive (sham) and hypertensive (2K–1W) mothers. The data is presented as mean±sem with n>4 placenta per group from 4 different litters. In sham animals, there was no difference between sexes in expression of any gene. Two way ANOVA showed renin mRNA was significantly decreased by maternal hypertension in both sexes (P<0.01). However, the AT1 receptor expression was only increased in the placenta of female fetuses in hypertensive mothers (P_{sex × treat}<0.05).

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3. The role of the renal RAS in programming models 

Given the renal and placental RAS play important roles in development and there is evidence that these systems are differentially expressed in male and female tissues, it is possible that the RAS may respond differently to adverse stimuli in the sexes contributing to the disparate outcomes observed in adulthood in male and female offspring.

Changes in the renal RAS have been identified in a variety of animal models of developmental programming. Overall, two major changes have been identified: firstly, during the period when the kidney is undergoing active nephrogenesis, activity of the RAS, including expression of the receptors, is decreased suggesting a role for the RAS in mediating the reduced nephron endowment and decreased kidney size in those models in which nephrogenesis is impaired. Secondly, after the completion of nephrogenesis, there is often an increase in renal RAS components which may provide a link to the onset of hypertension via increasing sodium retention [47]. Below we consider the evidence demonstrating alterations in the renal RAS in 3 different models of programming with particular reference to sex differences where possible. These studies have been summarised in Table 1, Table 2.

Table 1. Evidence of changes in the renal RAS before completion of nephrogenesis in studies of fetal programming.

Table 2. Evidence of changes in the renal RAS after completion of nephrogenesis in studies of fetal programming.

3.1. Prenatal glucocorticoid exposure 

Glucocorticoids are potent regulators of fetal growth and development. Mechanisms to tightly regulate fetal glucocorticoid exposure are of considerable importance, playing a role in organ maturation (kidney, brain), with excess glucocorticoids having been demonstrated to adversely alter fetal development [48]. We have used short term maternal glucocorticoid exposure in sheep, rats and most recently mice, to explore the mechanisms contributing to developmental programming. These models differ from many of the other animal models such as maternal undernutrition or placental insufficiency in that alterations in birth weight of the fetus do not occur demonstrating growth restriction is not an inevitable consequence of fetal programming [48].

Maternal glucocorticoid exposure can reduce nephron endowment and alter expression of the components of the RAS in the fetal kidney [48]. Short term glucocorticoid exposure, involving just 2–3 days of dexamethasone infusions to the mother, results in decreased nephron number in offspring of sheep [49], rats [50] and spiny mice [51]. We have also demonstrated that elevations in the natural glucocorticoid, cortisol (sheep, Moritz, unpublished) or corticosterone (rats, [9]) can also program a reduced nephron endowment. A common feature of these models is that the exposure occurred at the very early stages of development of the permanent metanephric kidney highlighting this time as a ‘critical window’ in which the kidney is particularly susceptible to insult.

In ovine fetuses at 130 days of gestation, a time when nephrogenesis is complete, there is an upregulation of gene expression for both the AT1 and AT2 receptors following prenatal exposure to glucocorticoids for 48h early in pregnancy [10]. Interestingly, the pattern of gene expression, when determined by in situ hybridisation, more closely resembled that of the neonatal lamb suggesting the glucocorticoids had caused premature maturation of the kidney [10]. In rats, maternal dexamethasone exposure on days 14 and 15 of pregnancy results in decreased expression of the AT1b and AT2 receptor but an increase in gene expression of the AT1a in the embryonic kidney on day 16. However, there was decreased expression of all 3 receptors in the kidney at day 20 of gestation, approximately 3 days after the infusion had been completed [52]. This highlights that some gene expression levels may be affected directly by the glucocorticoid exposure but after glucocorticoid levels return to normal, the gene expression levels may actually not return to normal for some considerable time, if at all. In the fetal sheep studies and embryonic rat studies, animals were not separated according to sex.

In rats, however, we have been able to identify sex specific changes in renal AT receptor gene expression in offspring following maternal corticosterone exposure. In male offspring at postnatal day 30, we found increased expression of both AT1a and AT1b receptor expression however, only AT1b was increased in females. However, only in females did the increased gene expression result in the elevations in protein levels suggesting differences in post-transcriptional activity between males and females [9]. Glucocorticoids have also been administered to the pregnant rat dam for a more extended period (5–7 days). In this case, growth restriction results and there is increased expression for renal angiotensinogen and renin but no changes in the AT receptors [53].

3.2. Uteroplacental insufficiency 

Uteroplacental insufficiency (UPI) is one of the major causes of growth restriction in the Western world. We have used a rat model of UPI induced by bilateral uterine vessel ligation on day 18 of pregnancy and found this results in growth restricted male and female offspring. However, only male offspring developed overt hypertension and metabolic disease [6], [7]. In the kidney we examined expression of the AT receptors and found in male offspring there tended to be increased expression of the AT1 receptor at 6 months of age [7], however in females there were no differences at either 6 or 18 months of age [6]. Others have shown using a similar rat model but starting the uteroplacental insufficiency at 14 days of gestation, that renal renin gene expression is decreased in the newborn suggesting inhibition of the RAS during development [54].

In the sheep, placental insufficiency induced by placental embolisation from 100 days results in decreased fetal body weight but no change in renal AT1 or AT2 receptor mRNA expression [8].

3.3. Maternal dietary manipulations 

A maternal low protein (MLP) diet throughout pregnancy has been used extensively in the rodent to examine programming. This regime has led to sex specific changes in the renal RAS. At birth, when the kidney is still developing in the rodent, there is strong evidence the RAS is suppressed with renin concentrations being lower and expression of the AT1 receptor reduced [13]. At birth, the levels of the AT2 receptor tended to be lower in offspring exposed to MLP although sexes were pooled. However, by postnatal day 30, there were significantly lower levels of AT2 receptor gene expression but only in females [55]. That study found that MLP had no effect on AT1 receptor expression although a follow up study by the same authors, which studied animals at 4 and 20 weeks, found decreased AT1a expression in both male and females but no difference in AT1b [56]. Changes in the RAS have also been seen in the kidneys of ovine fetuses following 50% global food restriction of the ewe during early to mid pregnancy. At 78 days of gestation, fetuses from nutrient restricted ewes had reduced AT1 receptor levels but by 135 days of gestation, renin levels were increased [45].

Together, these data suggest an important role for renal AT receptor gene expression that may contribute to programming outcomes. The receptor changes seen in adulthood may depend on the sex of the individual and the time at which receptor levels are studied.

Whilst nephron number and the renal RAS have been well studied in programming models, there is emerging evidence that many other aspects of renal development may be affected. Exciting studies using gene microarray technology have found nutrient restriction in the baboon during the first half of pregnancy affects multiple pathways including protein biosynthesis and cell signal transduction pathways [57]. This did not affect nephron endowment but instead suggested changes in the tubular compartments of the nephron.

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4. Conclusions 

In summary, it is likely that one of the major systems affected by an adverse intrauterine environment is the renal RAS which may respond differently to maternal perturbations dependent upon fetal sex. Given these findings, it is imperative that future programming studies examine sexes separately, even during fetal development. Inhibition of this system during fetal life may result in impaired kidney development and a permanent deficit in nephron endowment. However, other areas of kidney development such as the renal tubules may also be affected and needs to be thoroughly investigated. The observed increase in AT receptor levels seen in offspring probably reflects a compensatory increase to the reduced nephron endowment but may contribute to the development of hypertension. These findings in the kidney suggest the RAS can be greatly affected by maternal perturbations and thus further studies examining the role of the RAS in the placenta of programming models are warranted with particular reference to potential sex specific differences.

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Acknowledgements 

This work was supported by funding from the National Health and Medical Research Council of Australia and the Heart Foundation of Australia.

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Conflict of interest 

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

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