How the Kidney Is Impacted by the Perinatal Maternal Environment to Develop Hypertension

ABSTRACT

Environmental conditions during perinatal development such as maternal undernutrition, maternal glucocorticoids, placental insufficiency, and maternal sodium overload can program changes in renal Na⁺ excretion leading to hypertension. Experimental studies indicate that fetal exposure to an adverse maternal environment may reduce glomerular filtration rate by decreasing the surface area of the glomerular capillaries. Moreover, fetal responses to environmental insults during early life that contribute to the development of hypertension may include increased expression of tubular apical or basolateral membrane Na⁺ transporters and increased production of renal superoxide leading to enhanced Na⁺ reabsorption. This review will address the role of these potential renal mechanisms in the fetal programming of hypertension in experimental models induced by maternal undernutrition, fetal exposure to glucocorticoids, placental insufficiency, and maternal sodium overload in the rat.

The impact of adverse events during gestational life, on later cardio-renal health of the offspring is highlighted, implicating the importance of fetal life on long-term health.

INTRODUCTION

Renal Na⁺ excretory function is intrinsically accountable for the long-term control of blood pressure [1, 2]. A renal reduction in Na⁺ excretion, either by reduced glomerular filtration rate (GFR) or by increased tubular reabsorption of this electrolyte, causes hypertension. Besides genetic determinants, environmental conditions during perinatal development program changes in renal excretory function that lead to hypertension. Irreversible changes that occur during critical periods during early development are designated as the developmental programming of health and disease [3].

Low birth weight in human populations has been hypothesized to correlate to developmental programming of coronary heart disease [4] and hypertension [5] in later life. The hypothesis is based on studies that examined undernourished English populations born from 1911 to 1930 [4] and from 1935 to 1943 [5]. Proof of principle was first established by experimental models of undernutrition in the rat that demonstrated a direct link between adverse influences during fetal life and later increased cardiovascular risk, including the development of hypertension [6–10]. Increased fetal exposure to maternal glucocorticoids that cross the placenta are implicated in the etiology of cardiovascular risk that originate from insults during early life [6] with programmed changes in the fetal hypothalamic-pituitary-adrenal axis indicated to contribute to prenatal undernutrition-induced hypertension [11]. Fetal exposure to synthetic glucocorticoids leads to hypertension in the rat [12–14], requiring caution in their use for the treatment of preterm labor [15, 16]. However, in adequately nourished populations, placental insufficiency due to inadequate vascular adaptation at the uteroplacental interface, as observed in pregnancies complicated by preeclampsia, appears to be the main cause of intrauterine growth restriction (IUGR) and low birth weight [17]. Current models of placental insufficiency that program hypertension in the rat are induced via a reduction in flow introduced at the abdominal aorta below the kidneys and on both ovarian arteries [18] or by ligation of both uterine arteries [19, 20] to reduce uteroplacental flow in late gestation. Furthermore, sodium overload in the pregnant rat also causes placental dysfunction in a manner that resembles preeclampsia in the dam [21] and results in hypertension in the offspring [22–24]. In addition to clarifying the impact of preeclampsia, insight from the effect of maternal sodium overload during gestation per se on fetal development is critical because the human species exists mainly in industrialized areas and consumption of sodium in urbanized regions is approximately ten times greater relative to the amount of sodium consumed by our evolutionary ancestors [25].

Recent investigations confirm the correlation between birth weight and blood pressure in different populations including Chilean children [26], Brazilian children [27–29], and Chinese adults [30]. However, recent studies implicate that the quality of life during the early postnatal years [31–33] also exerts an underlying influence on the development of chronic disease in adult life. Yet, in experimental models of developmental insult, disruptions in the maternal environment may not always induce low birth weight although they may alter the function and physiology of the vital organs of the offspring in later life in a manner that also programs hypertension and increased cardiovascular risk.

Hypertension has been hypothesized to result from a congenital deficiency in nephron number, resulting in a reduced surface area for filtration that programs a subsequent reduction in GFR and an increase in sodium retention and hypertension [34]. Besides a reduction in glomerular surface area, however, hormonal regulation of renal hemodynamics by the renin-angiotensin system (RAS) can also contribute to a reduction in GFR and hypertension. There is evidence that the maternal environment may affect both cornerstones and reduce glomerular surface area and renal hemodynamics. Moreover, fetal exposure to an adverse maternal environment may 1) increase the expression of tubular apical Na⁺ transporters or of the basolateral membrane Na⁺ transporters, (Na⁺+K⁺)ATPase and Na⁺-ATPase, to increase filtered Na⁺ reabsorption and/or 2) increase renal superoxide production that may reduce renal medullary blood flow, contributing to the development of hypertension. This review will address the role of these potential renal mechanisms in the fetal programming of hypertension in experimental models of fetal programming induced by maternal undernutrition, maternal glucocorticoids, placental insufficiency, or maternal sodium overload.

NEPHRON NUMBER, GLOMERULAR HYPERTROPHY, AND DEVELOPMENTAL PROGRAMMING OF HYPERTENSION AND RENAL SUSCEPTIBILITY TO DISEASE

Renal volume assessed by ultrasound measurement is decreased in the IUGR fetus [35]. Furthermore, a reduction in the number of nephron is observed in African American and Caucasian individuals from the southeastern United States [36] and in Aborigine populations in Australia [37]. Numerous experimental models of developmental insult induced via maternal low protein [8], fetal exposure to maternal glucocorticoids [14], placental insufficiency [38], and maternal sodium overload [24] also demonstrate a reduction in nephron number that is associated with hypertension. However, findings relating a reduction in nephron number to increased blood pressure are correlative and may not directly indicate a causal role for a decrease in nephron endowment as the main determinant of hypertension. Yet, additional studies implicate that a congenital reduction in nephron number may enhance susceptibility to a secondary insult leading to greater injury or disease.

Nephron number affects the amount of glomerular surface area that is dependent on nephrogenesis when the kidney is not impacted by glomerulosclerosis. Glomerular surface area is one determinant of GFR that can modulate sodium reabsorption and indirectly regulate blood pressure. Whenever GFR is reduced, sodium reabsorption is increased. A reduction in nephron number that initiates during nephrogenesis in the rat is associated with a marked decrease in GFR and hypertension in later life [39], suggesting that a congenital reduction in nephron complement may significantly alter basal blood pressure regulation. Yet, in mice demonstrating a loss of one allele for glial cell line-derived neurotrophic factor that present with approximately 30% fewer nephrons, hypertension is not present when the mice are placed on a normal-salt diet. Yet, hypertension develops in response to a chronic salt load [40], indicating that a congenital reduction in nephron number enhances sensitivity to a secondary insult but may not directly affect the long-term regulation of blood pressure under basal conditions.

Nephrogenesis in the human begins by the 10th week postconception and ends by the 34th week. Although GFR is low at birth, considering the ratio of volume/body mass, normal term babies have a definitive number of nephrons at birth whereas preterm babies may continue nephrogenesis for weeks following birth (for reviews, see [41, 42]). Although renal maturation continues after preterm birth, attaining a continued increase in the generation of glomeruli, a greater percentage of morphologically abnormal glomeruli and a significantly larger cross-sectional area of the renal corpuscle are observed in preterm individuals, suggesting the development of renal hyperfiltration [43]. Thus, maturation of the kidney after birth in the human is associated with impaired nephrogenesis. In addition, due to continuation of nephrogenesis after delivery, preterm babies are more vulnerable than normal term babies to early adverse postnatal environmental influences such as medication [42]. In rats, the main animal species discussed in this review, nephrogenesis begins at the 12th day of fetal life and ends around the 10th day of postnatal life [44, 45]. Rodent models of developmental insult demonstrate sensitivity to an adverse insult that impairs nephrogenesis during pre- [8] and early postnatal life [46], indicating that the window of developmental vulnerability in the rat includes both the prenatal and early postnatal period. However, the normal extension of nephrogenesis into the postnatal period in the rat limits the usefulness of rodent models for understanding how disruptions during nephrogenesis affect later renal health.

Although a reduction in nephron number can be a determinant for decreased GFR, nephron number in rodent offspring of dams submitted to inadequate conditions during the perinatal period can remain unaltered, be reduced, or even increase (Table 1). Fluctuations in the pattern of GFR observed in experimental models of development insult can depend in part on the age of evaluation. Yet, the main contributor to disparate findings may be due to the fact that a reduction in nephron number is normally associated with glomerular hypertrophy (Table 1). The role of hypertrophic compensation on GFR could be verified by micropuncuture measurement of single nephron GFR, which as far as we know has not yet been performed in offspring of mothers adversely affected during gestation.

TABLE 1.

Effects of perinatal maternal environment on GFR and glomerular morphometry in the rat.

^a NN, number of nephrons.

The correlation between glomerular hypertrophy and a lower number of nephrons is observed in hypertensive white and African American individuals in the southeastern United States [47] and also in Senegalese men [48]. Chronic renal failure and microalbuminuria are more prevalent in low birth weight inhabitants of the southeastern United States [49] and Aborigines in the Australia's northern territories [50], respectively. Thus, these findings indicate that a reduction in nephron number may increase susceptibility to renal injury and disease. A comparison between two strain of rats, Lewis and Fisher 344, demonstrate that the latter, which exhibits a reduction in number of nephron, is more vulnerable to progressive chronic disease due to 5/6 nephrectomy than the former [51]. Similarly, rats submitted to IUGR by placental ischemia demonstrate an increase in renal vascular resistance, a reduction in GFR and renal injury in response to mild renal ischemia (15 min) followed by reperfusion that does not impair renal function and or result in renal injury in control counterparts [52]. Thus, these observations indicate that a congenital deficiency in nephron number may not be a unique determinant of hypertension in adult life; however, it does appear to contribute to a worsened prognosis of renal dysfunction in response to a secondary insult. Thus, additional molecular events in oligonephronic individuals contribute to the development of hypertension and renal disease.

Maternal Undernutrition and Nephron Number

The importance of timing of a developmental insult is indicated in experimental studies that vary exposure of the fetus to nutrient restriction during gestational life. Restriction of protein in the maternal diet from Days 1 to 11 of gestation does not alter the nephron number in male and female offspring. Yet, glomerular number, which is indicative of nephron number, is reduced in male offspring exposed to a maternal low-protein diet from Day 12 of gestation until birth [9] and male offspring exposed to global undernutrition throughout gestation [8]. Thus, the last 2 wk of gestation appears to serve as a crucial period whereby undernutrition can compromise nephrogenesis in the rat [7, 53]. Furthermore, exposure to a maternal low-protein diet during lactation in rat also compromises nephrogenesis, demonstrating that the crucial period of vulnerability extends into early postnatal life in the rat [54]. A reduction in nephron number is observed even when the maternal undernutrition is induced by restriction of only one nutrient in the rat such as protein [7], vitamin A [55], or iron [56], by global food restriction [53], or by a multideficient diet that is rich in carbohydrates that is not deficient in calories [10]. Compensatory glomerular hypertrophy is reported in the neonate rat that exhibits a nephron deficiency of 25% to 30% [53]. Glomerular hypertrophy is also observed in adult rats exposed to undernutrition during prenatal life [8, 10]. However, GFR is not reduced [8], indicating that glomerular hypertrophy that occurs following a reduction in nephron number sustains renal function and thus implicating other causative factors in the etiology of hypertension programmed in response to undernutrition during early life. Moderate maternal protein restriction programs hypertension associated with a reduction in nephron number in male, but not female, rat offspring [8, 57], suggesting a sex-specific impact of prenatal undernutrition on nephrogenesis. Kidney development and nephrogenesis depends in part on angiotensin II (Ang II) and is associated with glial cell-derived neurotrophic factor production [58–60]. Woods and coworkers [8] demonstrate that renin and Ang II expression is reduced in the kidney of male, but not female, rat offspring at birth following exposure to maternal undernutrition during fetal life [8, 57]. Thus, the sex difference in intrarenal RAS expression during development suggests that sex-specific adult outcomes related to nephron number and blood pressure may originate during fetal life. Although not completely understood, sex differences in gene expression in human and murine kidneys under baseline and disease conditions [61], if they could be further elucidated, could be utilized as preventative targets for sex-specific treatment of cardiovascular and renal disease. Besides RAS compromise, oligonephronia in undernourished rats is also attributed to apoptosis [62, 63]. Undernutrition in the sheep also compromises nephron number [64].

Fetal Exposure to Maternal Glucocorticoids and Nephron Number

Other models of developmental insult also demonstrate a reduction in nephron number. Prenatal exposure to dexamethasone, a synthetic glucocorticoid that is not appropriately metabolized by 11β-hydroxysteroid dehydrogenase 2 (11βHSD2) in the placenta, throughout pregnancy [12, 65] or from Days 15 to 18 of gestation leads to a reduction in nephron number in the offspring [13, 14]. However, only male offspring are hypertensive [14]. Maternal exposure to natural glucocorticoids induced by inhibition of 11βHSD2, the enzyme that serves as the barrier for fetal exposure to maternal glucocorticoids, also programs a reduction in nephron number [66]. As observed in models of maternal undernutrition, oligonephronia induced by inappropriate fetal exposure to maternal dexamethasone is also correlated with increased apoptosis [67].

Maternal Sodium Overload During Gestation and Nephron Number

Consumption of a high-salt diet by pregnant ewes during the final phase of nephrogenesis reduces the number of nephrons in the offspring [68]. Similarly in rats, exposure to maternal high dietary salt intake during pregnancy and lactation periods compromises nephrogenesis in the offspring [24]. Sodium overload may influence fetal development through its effects on decreasing maternal plasma renin [69] and Ang II [70] levels, correlating with reduced renal Ang II formation in the offspring during nephrogenesis [71]. The RAS is fundamental to nephrogenesis [58–60, 46]; therefore suppression of the RAS during fetal and early postnatal life may have long-term repercussions on renal function [23, 46]. Likewise, a 0.9% NaCl solution administered throughout pregnancy does not alter the number of nephrons, though it can arrest renal development [71]. Moreover, when the sodium overload progresses from gestation to weaning, it can be associated with an increase in the glomerulosclerosis index [72]. In addition, perinatal exposure to a maternal low-sodium diet during fetal life not only programs a reduction in nephron number, it is also induces high blood pressure in the offspring [24].

Placental Insufficiency and Nephron Number

When IUGR is induced by ligation of the two uterine arteries on Day 19 of gestation, it is associated with a reduction in the nephron number that is accompanied by an increase in markers of renal apoptosis [20]. Male, but not female, offspring are hypertensive in young adulthood [18, 73, 74]. Yet, in adult life, both male and female offspring demonstrate glomerular hypertrophy, whereas renal function is impaired to a greater degree in male compared to female counterparts [75]. Newborn piglets born with low birth weight compared to littermates also demonstrate a reduction in nephron number associated with a reduction in GFR and compromised urinary Na⁺ excretion [76]. Thus, IUGR affects nephron number regardless of the species studied and in a manner that is sex-specific despite the method of developmental insult.

To summarize, insults during fetal life often program a reduction in nephron number that corresponds to the development of hypertension in later life. Programming of reduced nephron number and hypertension is timing-specific and linked to the period of nephrogenesis. In addition, programming of reduced nephron number and hypertension may be sex-specific with the origins of sex differences in the fetal response to a developmental insult originating during fetal life due to sex-specific effects on gene expression that affect renal development. Although nephron number correlates to hypertension in these models of developmental insult, other causative factors may be important in the long-term regulation of impaired blood pressure.

THE RAS AND DEVELOPMENTAL PROGRAMMING OF HYPERTENSION

The RAS plays a key role in the long-term control of blood pressure through its actions on the kidney and the vasculature [77]. The RAS is a regulator of efferent arterial resistance contributing to the control of GFR by altering glomerular hydrostatic pressure, the main determinant of GFR [78]. Thus, a decrease in GFR mediated by programmed alterations in regulatory systems such as the RAS are implicated in the development and maintenance of hypertension programmed in response to a developmental insult.

Developmental Insults and the RAS

Langley-Evans and Jackson [79] report that plasma angiotensin converting enzyme-1 (ACE-1) activity is significantly increased in rats in offspring exposed to a casein-deficient diet during fetal life. The importance of the RAS in the developmental programming of hypertension in this model is demonstrated by the ability of the ACE inhibitor, captopril, to normalize blood pressure in undernourished offspring relative to their control counterparts [79]. Vehaskari et al. [80] report a reduction in plasma renin activity associated with an increase in plasma aldosterone levels in young rats exposed to maternal low protein during fetal life. Renal expression of the Ang II receptor (AT₁R) is also increased in this model [81] with the relative importance of the RAS demonstrated by normalization of the blood pressure by chronic RAS blockade [82]. Alterations in expression of the RAS are also common to other models of developmental insult [83], and blockade of the RAS also abolishes hypertension in offspring of dams submitted to placental insufficiency [84]. Renin and ACE mRNA expression are increased in the kidneys and adipose tissue of adult offspring exposed to maternal dexamethasone, a synthetic steroid, during fetal life [85]. Changes in RAS components are also observed in the offspring exposed to maternal sodium overload during fetal or early postnatal life [24, 72]. However, Mesquita et al. [86] report that exposure to a low-protein diet throughout pregnancy in the rat reduces expression of the Ang II receptors, AT₁R and AT₂R. The reduction in AT₁R is paralleled by a reduction in the expressions of janus kinase 2, which is a non-receptor-type tyrosine kinase that regulates signal transducers and activators of transcription. In the fetal brain of undernourished mice, components such as mRNA of angiotensinogen and ACE-1 are increased, while mRNA levels of AT₂R are decreased. Hypomethylation of the CpG islands in the promoter regions of ACE-1 gene and upregulation of the microRNAs, mmu-mir-27a and 27b, which regulate ACE-1 mRNA translation, are also seen in the fetal brain of prenatal undernourished mice [87]. These findings give support that changes in DNA methylation and microRNA are key mediators of hypertension at adult life. Furthermore, intracerebroventricular blockade of the central actions of the RAS ameliorates hypertension in low-protein offspring, implicating a central role for the RAS in the programming of hypertension [88].

To summarize, classical hormones that regulate GFR such as Ang II contribute to hypertension programmed by prenatal undernutrition [79, 80, 86], maternal sodium overload during pregnancy and lactation [24, 72], placental insufficiency [84], and fetal exposure to maternal glucocorticoids during Day 13 of gestation to term [85]. Although insight from these studies implicate an important role for the RAS in the developmental programming of hypertension, the exact role of Ang II in the etiology of programmed hypertension and impaired renal hemodynamics is still not clearly demonstrated from reports published thus far. However, the impact of the RAS on programming of hypertension in response to a developmental insult may result from its influence on sodium reabsorption in the proximal tubule.

TUBULAR SODIUM TRANSPORTERS AND HYPERTENSION

The bulk of sodium reabsorption in the apical membrane of proximal tubule epithelium is largely carried out by the Na⁺-H⁺-transporter, while parallel transport of sodium in the basolateral membrane is mainly carried out by the (Na⁺+K⁺)ATPase and Na⁺-ATPase transporters. In the thick ascending limb and distal tubule, the bulk of sodium transport in the apical membrane involves the Na⁺K⁺2Cl⁻ (NKCC2) and Na⁺Cl⁻ cotransporters whereas parallel transport in the basolateral membrane is mainly conducted via the (Na⁺+K⁺)ATPase transporter. The (Na⁺+K⁺)ATPase transporter is an epithelial polarized enzyme that maintains overall intracellular Na⁺ equilibration and creates the electrochemical gradient for electrolyte reabsorption in the basolateral membrane of the tubular kidney. Less widespread, the α-subunit of Na⁺-ATPase was recently purified and cloned from the basolateral membrane of epithelial bowel of guinea pig [89]. This enzyme is responsible for approximately 10% of the reabsorption of filtered sodium [90] in the proximal tubule, and it is also designated as the ouabain-insensitive Na⁺-ATPase transporter or a second sodium pump. Although recently cloned, the role of Na⁺-ATPase in sodium reabsorption in the proximal tubule has been extensively investigated [91–93] and implicated in the development of hypertension in the spontaneously hypertensive rat (SHR) [89, 94]. Specifically, increased activity of the NKCC2 transporter along the thick ascending limb of the Milan hypertensive rat [95] and increased activity of Na⁺-H⁺-transporter along the proximal tubule in juvenile SHRs [96–98] highlights the importance of these apical membrane Na⁺ transporters in the maintenance of hypertension. Sodium ion reabsorption along the proximal tubule plays a remarkable role in the development of hypertension in the SHR [96–98] with Na⁺ reabsorption increased during the juvenile age [96] and with activity reduced in the adult SHR [96, 98], implicating that temporal changes in sodium transporter expression may contribute to the etiology and maintenance of hypertension.

Maternal Undernutrition, Prenatal Glucocorticoid Exposure, and Tubular Sodium Transporters

Alterations in tubular Na⁺ reabsorption may be one mechanism by which exposure to a developmental insult programs an increase in blood pressure. Renal mRNA expression of the α1 and β1 subunits of the (Na⁺+K⁺)ATPase are increased in adult rat offspring exposed to undernutrition during fetal life [99]. This alteration in sodium transport expression is associated with the development of hypertension, implicating a role for impaired sodium transport in the etiology of hypertension programmed in response to fetal undernutrition [99]. Maternal undernutrition also programs a reduction in renal expression of 11βHSD2 mRNA, the enzyme that catalyzes the inactivation of cortisol to corticosterone in the rat (cortisol in humans) that coincides with an increase in renal expression of the glucocorticoid receptor mRNA [99]. Glucocorticoids increases (Na⁺+K⁺)ATPase activity in the thick ascending limb [100]. Thus, these hormones could contribute to the developmental programming of hypertension in prenatal undernourished rats.

Bumetanide-sensitive cotransporter NKCC2 mRNA and protein expression are increased in the thick ascending limb [101, 102] of rats exposed to prenatal undernutrition. In addition, the thiazide-sensitive Na⁺Cl⁻ cotransporter located in the distal convoluted tubule is also increased in animals exposed to undernutrition during fetal life [101, 102]. However, increases in (Na⁺+K⁺)ATPase activity in later life are preceded by a reduction in whole kidney (Na⁺+K⁺)ATPase activity at 1 mo of age in rats submitted to a maternal low-protein diet during prenatal life, indicating that developmental insults may program temporal changes in expression of tubular sodium transporter activity [103]. The importance of glucocorticoids in the programming of altered sodium transporter expression is demonstrated in experimental studies whereby changes in expression of the basolateral or apical membrane sodium transporters are programmed by direct prenatal exposure to inappropriate levels of maternal dexamethasone (Table 2). Dexamethasone administered in the second half of pregnancy [85] or during four critical days of nephrogenesis in the rat (Days 15 to 18 of pregnancy) [104, 105] programs a marked increase in sodium transporter expression. These programmed changes in expression include an increase in mRNA expression of the α1 subunit of (Na⁺+K⁺)ATPase [85], expression of NHE3 on the brush border membrane vesicles of the proximal tubule [102], and expression of NKCC2 and Na⁺Cl⁻ cotransporter in the renal cortex [104]. These changes in transporter expression are correlated with increased blood pressure in these models of developmental insult [104, 105]. Thus, these studies indicate a strong role for programmed alterations in sodium transport expression in the developmental programming of hypertension.

TABLE 2.

Effect of perinatal maternal environment on renal Na⁺ transporters in the rat.

Based on evidence that changes in Na⁺-ATPase activity may be involved in hypertension, Na⁺-ATPase activity has been investigated in offspring exposed to maternal undernutrition during perinatal life [54, 106–108]. In rats exposed to a multideficient diet during prenatal life, Na⁺-ATPase activity is increased at 30 and 60 days of age or during the establishment of programmed hypertension [108]. However, Na⁺-ATPase activity is unchanged at an age of 90 days [108]. The activity of this enzyme in the proximal tubule is regulated in part by Ang II with protein kinase C and A contributing as intracellular downstream mediators [109]. Rats exposed to a multideficient diet during prenatal life demonstrate a decrease in expression and activity of protein kinase C and an increase in expression and activity of protein kinase A in the proximal tubule membranes associated with a loss of responsiveness to physiological concentrations of Ang II in adult life [108]. Besides hyporesponsiveness to Ang II, these animals present a reduction in activity of the (Na⁺+K⁺)ATPase transporter [106], suggesting a reduction in proximal tubule Na⁺ reabsorption in adult animals. Taken together, these findings demonstrate the following: first, that exposure to a multideficient diet during prenatal life programs temporal changes in Na⁺ transporters similar to what is observed in the SHRs [96–98], and second, that increases in Na⁺ reabsorption may precede the development of hypertension in prenatal undernourished rats.

Increases in Na⁺ transporters, either in prenatal undernourished rats [99, 101, 102] or in prenatal rats exposed to maternal dexamethasone is correlated to increased levels of blood pressure [102, 104]. Bilateral renal denervation during adult life abolishes the increase in NKCC2 and Na⁺Cl⁻ expression in the renal cortex in conjunction with hypertension programmed by prenatal exposure to dexamethasone [104]. Thus, this study suggests that the renal nerves may contribute to the etiology of hypertension programmed by perinatal exposure to glucocorticoids via alterations in Na⁺ tubular transport.

OXIDATIVE STRESS AND THE DEVELOPMENTAL PROGRAMMING OF HYPERTENSION

Oxidative stress involves an imbalance in reactive oxygen species and may include the production of increased levels of hydrogen peroxide, superoxide anion radicals, and hydroxyl anions. One consequence of superoxide elevation in the renal medulla is a reduction in medullary blood flow and an increase in Na⁺ reabsorption leading to sustained hypertension [110, 111]. A component of superoxide's action in renal tissue is mediated by a reduction in local nitric oxide levels [112] that can increase Na⁺ reabsorption due to augmentation of NKCC2 activity in the ascending limb of Henle [113]. Furthermore, it is known that the oxidative stress alters the interplay between the mineralocorticoid receptor and one of its intracellular signaling molecules, the small guanosine triphosphatase Rac1, to increase Na⁺ reabsorption and induce hypertension [114]. Because Rac1 is also a NADPH-oxidase subunit, the action of aldosterone, the main mineralocorticoid, results in an increase in oxidative stress resulting from NADPH-oxidase activation and increased Na⁺ reabsorption throughout upregulation of epithelial sodium channels, the Na⁺Cl⁻ cotransporter and (Na⁺+K⁺)ATPase transporter located in the distal portion of the tubule [115].

Maternal Undernutrition, Placental Insufficiency, and Maternal Sodium Overload and Renal Oxidative Stress

Oxidative stress is increased in the kidneys of prenatal undernourished rats [106, 108, 116–118] as well as in the offspring of mothers submitted to placental insufficiency [119] and sodium overloads [120, 121]. Hypertension in male offspring of mothers submitted to placental insufficiency is abolished by treatment with tempol, a mimetic of superoxide dismutase [118], indicating a key role for oxidative stress in the etiology of programmed hypertension. Suppression of the RAS during nephrogenesis may contribute to the increase in oxidative stress in adult life. Blockade of the RAS during the postnatal period of the rat that corresponds to nephrogenesis programs hypertension in the adult rat that is reduced by treatment with tempol [122]. An increase in renal markers of oxidative stress are also observed in different animal models of developmental insult [106, 108, 116–118], including adult offspring exposed to prenatal undernutrition [79, 80], placental insufficiency [84], or models that involve suppression of the RAS during early life [8, 71, 83, 123]. Importantly, increased oxidative stress is linked to an elevation in blood pressure in the male rat relative to the female rat [119, 122, 124], suggesting that oxidative stress may contribute to the sexual dimorphic control of blood pressure and cardiovascular risk induced by a prenatal insult.

Oxidative stress is appropriately considered a cause, a consequence, or a potentiating factor in the development of hypertension (for a review, see [125]). Pretreatment of undernourished mothers during gestation with antioxidants prevents the development of hypertension in the offspring [107]. In addition, maternal undernutrition is associated with an increase in placental oxidative stress, indicating that exposure to oxidative stress has its origins in early life [106]. Moreover, epigenetic processes may contribute to the increase in oxidative stress that is responsible for endothelial dysfunction [126] in prenatal undernourished rats. The efficacy of antioxidant tools to prevent renal dysfunction reinforces the role of oxidative stress as a cause of perinatal programmed hypertension.

INTERVENTIONS TO MITIGATE PROGRAMMED OUTCOMES

Several studies indicate that early interventions may be preventative against the fetal programming of later renal dysfunction or hypertension. Maternal treatment with the antioxidant α-tocopherol during lactation in prenatally undernourished rats [123] or cross-fostering pups at birth of placental insufficient dams [73] prevents oligonephronia. Oligonephronia induced by maternal undernutrition is also prevented by administration of ouabain in parallel with maternal undernutrition during pregnancy. Ouabain, an inhibitor of (Na⁺+K⁺)ATPase transporters, increases intracellular calcium and prevents apoptosis to ameliorate reductions in nephron endowment [62, 63]. Treatment with tempol during pregnancy prevents prenatal glucocorticoid-induced aorta dysfunction and hypertension [127] in addition to endothelial dysfunction programmed by undernutrition in the prenatal rat [126]. Moreover, rats prenatally treated with dexamethasone and cross-fostered to mothers on a diet rich in n-3 long-chain polyunsaturated fatty acids (n-3 PUFA) do not demonstrate hyperleptinemia or develop hypertension [128]. Supplementation with n-3 PUFA attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney of 5/6 nephrectomized rats [129], suggesting that in addition to its actions to reduce leptin, n-3 PUFA may also contribute to a reduction in renal oxidative stress. Thus, the benefit of n-3 PUFA administered during lactation to rats prenatally exposed to dexamethasone [128] may also involve attenuation of oxidative stress and provides further evidence implicating a role for oxidative stress in the early origins of hypertension induced in response to adverse influences that originate from the maternal environment.

The critical period for development of tubular Na⁺ transporters includes not only the prenatal period, but also early postnatal life in the rat (for a review, see [130]). Several studies strongly suggest that the period for developmental programming of Na⁺ transporters extends beyond lactation in the rat: treatment with enalapril, an ACE inhibitor [131] or exposure to a low-sodium diet [132] for a period of 3 wk after weaning prevents adult hypertension in rats expose to undernutrition during prenatal life. Treatment with an ACE inhibitor from 2 to 6 wk of life changes the course of hypertension in SHRs in later life [133], and enalapril administered for a period of 3 wk after weaning reduces activity of (Na⁺+K⁺)ATPase and Na⁺-ATPase in the proximal tubule [120]. Despite these promising effects, it is important to emphasize that ACE inhibitors and AT₁R antagonists are potential teratogenic agents to humans [134, 135] and thus, their use is contraindicated during pregnancy. Caveats include the numerous studies demonstrating that the use of RAS inhibitors program adverse effects when administered prenatally in the rat [122, 136–138] as compared to their action when administered after weaning [120, 131, 133]. Taken together, these studies indicate early lifestyle changes including antioxidant supplementation, a balanced diet, salt restriction, or even therapeutic maneuvers can serve as potential targets and may prove effective in counteracting the adverse programming of chronic health in the event that adverse environmental influences during development cannot be avoided.

CONCLUSIONS

Although it is clear that nephrogenesis can be compromised by perinatal responses to an adverse maternal environment and that renal hemodynamics may be affected by altered regulation of classic hormones such as Ang II, GFR is not always reduced in experimental models of programmed insult (Table 1), in part due to the development of glomerular hypertrophy. Thus, a congenital reduction in the number of nephrons presents as a status that worsens renal function in the face of later insults [36, 48, 49, 51, 52, 139]. On the other hand, molecular programming events such as changes in tubular sodium transporters (Table 2) and increased renal oxidative stress seem to be crucial in the development of programmed hypertension (Fig. 1). Therefore, hypertension induced in response to adverse maternal influences during fetal life may involve a reduction in GFR and/or an increase in sodium reabsorption (Fig. 1). Early interventions to ensure proper nephrogenesis and reduce inappropriate increases in renal oxidative stress may be potential targets in the development of therapeutic agents in the prevention of later programmed renal dysfunction.

FIG. 1.

Renal role in the development of hypertension in the offspring of mothers showing a perturbed maternal environment. Black line, programmed alteration; dashed line, inhibition (indicative of early intervention that could prevent renal dysfunction). GFR is not always predictable due to glomerular hypertrophy (see Table 1).