Differential hepatic lobar gene expression in offspring exposed to altered maternal dietary protein intake

Increased plasma fibrinogen concentrations are a recognized risk factor for coronary heart disease, and increased fibrinogen levels in adults are associated with parameters of reduced early growth. We studied fibrinogen gene expression in adult offspring of dams fed either a 20% (control) or an 8% protein diet [maternal low-protein (MLP) rats] during pregnancy and lactation and determined whether any effects were consistent between left and right liver lobes, since the fetal liver has a unique blood supply that produces differential stimuli to the left and right lobes. In MLP offspring, there was a reduction in all three fibrinogen mRNA copy numbers in the left liver lobe [left vs. right lobes for alpha-, beta-, and gamma-fibrinogen (x10(6) copies/ng total RNA): 8.04 vs. 23.16, P<0.001; 4.74 vs. 13.07, P<0.001; and 4.61 vs. 16.38, P = 0.007, respectively], with a parallel reduction in fibrinogen concentration in the left liver lobe (8.53+/-0.33 vs. 10.41 +/-0.65 arbitrary units, P = 0.014, left and right lobes, respectively). No such effect was observed in offspring of control dams. To investigate the underlying mechanism, glucocorticoid receptor function and mRNA levels were studied, since expression of fibrinogen genes is regulated by glucocorticoid hormones. The binding affinity of the high-affinity glucocorticoid receptor was reduced only in the left liver lobe of the MLP offspring (P = 0.02, left. vs. right), with a parallel reduction in this lobe in glucocorticoid receptor mRNA level (P = 0.006, left vs. right). In conclusion, maternal dietary protein restriction reduces fibrinogen gene expression, fibrinogen protein, and mRNA level and binding affinity of glucocorticoid receptors only in the left liver lobe of the adult offspring.     

Prenatal programming of adult blood pressure: role of maternal corticosteroids

Both maternal glucocorticoid administration and maternal dietary protein or food restriction in pregnancy cause fewer nephrons and hypertension in the adult offspring. The purpose of these studies was to determine the extent to which nutritional factors contribute to programming of offspring hypertension by maternal glucocorticoids. Pregnant rats were treated with dexamethasone (100 microg x kg(-1) x d(-1) sc) on days 1-10 (ED) or days 15-20 (LD) of pregnancy. Additional groups of pregnant animals were pair fed to the early (EDPF) and late (LDPF) dexamethasone-treated groups, and another group was untreated or given vehicle (C). The dams treated with dexamethasone reduced their food intake and lost or failed to gain a normal amount of weight during treatment; body weights of ED dams caught up to normal after the treatment period, whereas those of LD dams did not. In adulthood ( approximately 21 wks), chronically instrumented male offspring of ED had normal blood pressures (125 +/- 2 mmHg vs. 126 +/- 1 mmHg in C), whereas LD offspring were hypertensive (136 +/- 3 mmHg). However, LDPF offspring were equally hypertensive (134 +/- 2 mmHg). Glomerular filtration rates normalized to body weight were not significantly different among groups. Qualitatively similar results were found in female offspring. Thus the long-term effects of maternal glucocorticoid administration at this dose on offspring's blood pressure may, in large part, be accounted for by the reduction in maternal food intake. These data suggest that maternal glucocorticoids and maternal food or protein restriction may, at least in part, share a common mechanism in programming offspring for hypertension. The window of sensitivity of future offspring blood pressure to either maternal insult coincides with nephrogenesis in the rat, suggesting that impaired renal development could play an important role in this programming.     

Glucocorticoid Effects on the Programming of AT1b Angiotensin Receptor Gene Methylation and Expression in the Rat

Adverse events in pregnancy may ‘programme’ offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11β-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence.     

Prenatal high-salt diet in the Sprague-Dawley rat programs blood pressure and heart rate hyperresponsiveness to stress in adult female offspring

Several animal models have been developed to study fetal programming of hypertension. One model involves feeding high-salt (HS) diet to rats before and during pregnancy, during lactation, and after weaning for 10 days. In the present investigation, we limited HS diet to the prenatal period in an attempt to find a narrower critical window for fetal programming. The HS diet did not result in low-birth weight offspring. In the adult offspring, radiotelemetry was used to assess blood pressure and heart rate in the conscious unstressed state. As adults, the HS offspring were not hypertensive compared with normal-salt (NS) control animals. However, the pressor and tachycardic responses to 1-h of restraint were significantly enhanced in HS female offspring, and recovery after restraint was delayed. This was accompanied by an increase in relative expression of corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus during basal and stressed conditions. There was no augmented stress response or relative increase in CRH mRNA in adult HS male offspring. When challenged with 1 wk of 8% NaCl diet as adults, neither HS male nor female offspring exhibited salt sensitivity compared with NS groups. These data show that a high-salt diet limited to the prenatal period is not sufficient to program hypertension in adult offspring. However, this narrower critical period is sufficient to imprint a lasting hyperresponsiveness to stress, at least in adult female offspring. These data indicate that excessive maternal salt intake during pregnancy can adversely affect the cardiovascular health of adult offspring.     

Differential effects of maternal nutrient restriction through pregnancy on kidney development and later blood pressure control in the resulting offspring

The mechanisms whereby maternal nutritional manipulation through pregnancy result in altered blood pressure in the offspring may include changes in fetal and newborn and adult renal prostaglandin (PG) synthesis, metabolism, and receptor expression. Since the postnatal effects of nutrient restriction on the renal PG synthesis and receptor system during nephrogenesis in conjunction with nephron numbers and blood pressure have not been evaluated in the rat, the present study examined the effect of reducing maternal food intake by 50% of ad libitum through pregnancy on young male rats. Six control-fed mothers and eight nutrient-restricted pregnant rats with single litter mates were used at each sampling time point, most of which occurred during nephrogenesis. Offspring of nutrient-restricted dams were lighter from birth to 3 days. This was accompanied by reduced PGE2, with smaller kidneys up to 14 days. Nutrient restriction also decreased mRNA expression of the PG synthesis enzyme, had little effect on the PG receptors, and increased mRNA expression of the degradation enzyme during nephrogenesis and the glucocorticoid receptor in the adult kidney. These mRNA changes were normally accompanied by similar changes in protein. Nephron number was also reduced from 7 days up to adulthood when blood pressure (measured by telemetry) did not increase as much as in control offspring during the dark, active period. In conclusion, maternal nutrient restriction suppressed renal PG concentrations in the offspring, and this was associated with suppressed kidney growth and development and decreased blood pressure.     

Fetal and postnatal zinc restriction: sex differences in the renal renin-angiotensin system of newborn and adult Wistar rats

This study aimed to evaluate renal morphology and the renal renin-angiotensin system in 6- and 81-day-old male and female offspring exposed to zinc deficiency during fetal life, lactation and/or postnatal growth. Female Wistar rats were fed low- or control zinc diets from pregnancy to offspring weaning. Afterwards, offspring were fed a low- or a control zinc diet until 81 days of life. In 6- and/or 81-day-old offspring, we evaluated systolic blood pressure, renal morphology, renal angiotensin II and angiotensin 1-7 concentration, and AT1 and AT2 receptors and angiotensin-converting enzymes protein and/or mRNA expression. At 6 days, zinc-deficient male offspring showed decreased glomerular filtration areas, remodelling of renal arteries, greater number of renal apoptotic cells, increased levels of Angiotensin II, higher Angiotensin II/Angiotensin 1-7 ratio and increased angiotensin-converting enzyme 1, AT1 and AT2 receptors mRNA and/or protein expression. Exacerbation of the renal Ang II/AT1 receptor axis and remodelling of renal arteries were also observed in adult zinc-deficient male offspring. An adequate zinc diet during post-weaning life did not improve all the alterations induced by zinc deficiency in early stages of development. Female offspring would appear to be less sensitive to zinc deficiency with no increase in blood pressure or significant alterations in renal morphology and the renin-angiotensin system. Moderate zinc deficiency during critical periods of prenatal and postnatal development leads to early morphological renal alterations and to permanent and long-term changes in the renal renin-angiotensin system that could predispose to renal and cardiovascular diseases in adult life.     

Role of maternal glucocorticoid inducible kinase SGK1 in fetal programming of blood pressure in response to prenatal diet

Maternal stress and malnutrition modify intrauterine fetal development with impact on postnatal blood pressure, nutrient, water, and electrolyte metabolism. The present study explored the possible involvement of maternal serum- and glucocorticoid-inducible kinase (SGK)-1 in fetal programming of blood pressure. To this end, wild-type (sgk1(+/+)) male mice were mated with SGK1 knockout (sgk1(-/-)) female mice, and sgk1(-/-) males with sgk1(+/+) females, resulting in both cases in heterozygotic (sgk1(-/+)) offspring. Following prenatal protein restriction, the offspring of sgk1(+/+) mothers gained weight significantly slower and had significantly higher blood pressure after birth. Moreover, a sexual dimorphism was apparent in fasting blood glucose and plasma corticosterone concentrations, with higher levels in female offspring. In contrast, prenatal protein restriction of sgk1(-/-) mothers had no significant effect on postnatal weight gain, blood pressure, plasma glucose concentration, or corticosterone levels, irrespective of offspring sex. Plasma aldosterone concentration, urinary flow rates, and urinary excretions of Na(+) and K(+) were not significantly modified by either maternal genotype or nutritional manipulation. In conclusion, maternal signals mediated by SGK1 may play a decisive role in fetal programming of hypertension induced by prenatal protein restriction.     

感觉神经损伤性盐敏感性高血压大鼠心、肾AT1R的表达

目的对感觉神经损伤性盐敏感性高血压大鼠的心肌、肾脏组织中的血管紧张素Ⅱ1型受体（AT1R）在mRNA和受体水平的表达进行检测,探讨AT1R与盐敏感性高血压的关系。方法用乳鼠皮下注射辣椒辣素法建立模型。哺乳期后,大鼠被随机分成4组：对照＋正常盐饮食组（CON-NS）;对照＋高盐饮食组（CON-HS）;辣椒辣素＋正常盐饮食组（CAP-NS）;辣椒辣素＋高盐饮食组（CAP-HS）。至7周龄（分组饲养后第4周）处死大鼠,免疫组织化学方法和反转录-聚合酶链式反应（RT-PCR）分别检测大鼠心肌和肾脏AT1R蛋白,以及AT1 R mRNA的表达。结果①Wistar大鼠在给予不同程度的感觉神经损伤和饲料干预后,各组大鼠尾部收缩压均有明显增加,最终CAP-HS组的尾收缩压显著高于其他三组（P〈0.01）。②免疫组织化学结果显示,CAP-HS组组织有显著的AT1R蛋白表达（P〈0.01）;CON-HS组肾脏、心肌组织中AT1R蛋白表达高于CON-NS组（P〈0.05）。③RT-PCR检测基因表达,与对照组CON-NS相比,实验组CAP-HS的AT1R mRNA表达显著升高（P〈0.01）;CON-HS组肾脏、心肌组织中AT1 R mRNA表达有显著性（P〈0.05）。结论感觉神经损伤性盐敏感性高血压大鼠心、肾AT1R表达升高,AT1R表达水平的差异可能与盐敏感性高血压的形成有关。     

High sucrose intake during gestation increases angiotensin II type 1 receptor-mediated vascular contractility associated with epigenetic alterations in aged offspring rats

Accruing evidence have confirmed that the fetal programming in response to adverse environmental in utero factors plays essential roles in the pathogenesis of hypertension in later life. High sugar intake has been accepted worldwide in everyday life diet and becomes the critical public health issue. Our previous studies indicated that intake of high sucrose (HS) during pregnancy could change the vascular reactivity and dipsogenic behavior closely associated with abnormal renin-angiotensin system (RAS), to increase the risk of hypertension in adult offspring. In the present study, we tested the hypothesis that maternal HS intake in pregnancy may further deteriorate the Ang II-induced cardiovascular responses in the aged offspring. HS intake was provided to pregnant rats throughout the gestation. Blood pressure (BP) in conscious state and vascular contractility in vitro were measured in 22-month-old aged offspring rats. In addition, mRNA and protein expressions and epigenetic changes of Ang II type 1 receptor (AT₁R) gene in blood vessels were determined with the methods of real-time RT-PCR, Western blotting, and Chromatin Immunoprecipitation Assay (CHIP). Results showed that, in the aged offspring, maternal HS intake during gestation would cause the elevation of basal BP which could be diminished by losartan. Although the circulatory Ang II was not changed, levels of local Ang II were significantly increased in blood vessels. In addition, prenatal HS exposure would significantly enhance the AT₁R-mediated vasoconstrictions in both aorta and mesenteric arteries of the aged offspring. Moreover, in the aged offspring of prenatal HS exposure, mRNA and protein expressions of AT₁R gene in both large and small blood vessels were significantly increased, which should be closely associated with the changes of epigenetic mechanisms such as histone modifications. Collectively, we proposed that maternal HS intake during gestation would cause abnormal BP responses mediated via the enhancement of vascular RAS, together with the increased expression of AT₁R gene related to the its epigenetic changes, which would actually lead to the overt phenotype of hypertension in the aged offspring.     

Streptozotocin-induced diabetes in the pregnant rat reduces 11 beta-hydroxysteroid dehydrogenase type 2 expression in placenta and fetal kidney

Several epidemiological and animal studies have shown that the offsprings of diabetic mothers have higher incidences of glucose intolerance, obesity, insulin resistance, and hypertension in later life. It is well known that glucocorticoid metabolism plays a crucial role on several adult disease originated from fetal environment. The aim of this study was to investigate the relation between diabetic pregnancy and glucocorticoid metabolism of both mother and fetus, focusing on the 11 beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2. A model of diabetic pregnancy was made by intravenous injection of streptozotocin (35 mg/kg body weight) to Sprague-Dawley rats, and blood and tissue samples were collected on day 20 of pregnancy. In the diabetic group, expression of 11 beta-hydroxysteroid dehydrogenase type 2 in placentas and fetal kidneys was decreased remarkably. Corticosterone levels of diabetic mothers were lower than those of control rats. Despite the differences in maternal corticosterone levels, fetal levels of corticosterone did not differ between the groups. Our results lend support to the concept that diabetic pregnancy imprints glucocorticoid regulation in these fetuses, which may contribute to their increased incidence of higher blood pressure as adults.     

Effects of corticosterone deficiency and its replacement on Leydig cell steroidogenesis

Clinical and experimental studies have shown the adverse effects of glucocorticoid deficiency/metyrapone treatment on testicular Leydig cell testosterone production. However, molecular mechanisms that underlie the effects of glucocorticoid deficiency on Leydig cell steroidogenesis are not yet determined. Therefore, the present study was designed to assess the mechanism of this phenomenon. Following metyrapone-induced corticosterone deficiency, serum testosterone, and Leydig cell 14C-glucose oxidation were decreased. StAR mRNA and protein levels were significantly increased in Leydig cells of corticosterone-deficient animals. mRNA levels and the specific activities of P(450)scc and 17beta-HSD were decreased by corticosterone deficiency, whereas the activity and mRNA of 3beta-HSD were increased. Simultaneous administration of corticosterone prevented its deficiency-induced changes in Leydig cells. Our results show that metyrapone-induced corticosterone deficiency impairs Leydig cell testosterone production by decreasing the activities of steroidogenic enzymes and their mRNA expression and glucose oxidation.     

Maternal resveratrol therapy protected adult rat offspring against hypertension programmed by combined exposures to asymmetric dimethylarginine and trimethylamine-N-oxide

Resveratrol, a phytochemical, has shown antioxidant properties and potential benefits in hypertension. Asymmetric dimethylarginine (ADMA)-related nitric oxide deficiency and gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) have been linked to hypertension. We aimed to test whether maternal resveratrol therapy would protect adult offspring against hypertension programmed by prenatal exposure to ADMA and TMAO. Pregnant Sprague-Dawley rats received ADMA 10 mg/kg/day (A), TMAO 0.65 mg/hr (T), ADMA+TMAO (AT), or vesicle (CV). One group of ADMA+TMAO-exposed rats received 50 mg/L of resveratrol in drinking water during pregnancy and lactation periods (ATR). Male offspring (n = 8/group) were assigned to five groups: CV, A, T, AT, and ATR. Rats were killed at 12 weeks of age. ADMA exposure caused the elevation of blood pressure in 12-week-old male offspring, which was exacerbated by TMAO exposure. Treatment with resveratrol rescued hypertension programmed by combined ADMA and TMAO exposure. This was accompanied by alterations in the compositions of gut microbiota and increased fecal butyrate levels. Both the abundance of the butyrate-producing genera Lachnospiraceae and Ruminococcaceae were augmented by resveratrol. Meanwhile, resveratrol therapy significantly increased the abundance of the Cyanobiaceae and Erysipelotrichaceae families. Moreover, the protective effects of resveratrol were related to the mediation of the renin-angiotensin system . Our data provide new insights into the protective mechanisms of resveratrol against hypertension programmed by ADMA and TMAO, including regulation of gut microbiota and their metabolites, the renin-angiotensin system, and nitric oxide pathway. Resveratrol might be a potential reprogramming strategy to protect against the hypertension of developmental origins.     

Prenatal diet determines susceptibility to cardiac ischaemia-reperfusion injury following treatment with diethylmaleic acid and N-acetylcysteine

Fetal undernutrition programmes increased risk of developing cardiovascular disease in adult life. We hypothesized that prenatal protein restriction would impair recovery in post-ischaemic cardiac function in adult offspring through antioxidant-mediated processes. Pregnant Wistar rats were fed control or maternal low protein diets (MLP) throughout gestation. The offspring of these rats were treated with either saline, N-acetylcysteine (NAC), diethylmaleate (DEM), or both NAC and DEM to manipulate glutathione status at 6 months of age. Hearts were rapidly excised and retro-perfused (Langendorff) to assess isolated cardiac function before (baseline), and during 30 min global ischaemia and 60 min reperfusion. Hearts from adult rats exposed to a MLP diet in utero suffered greater cardiac dysfunction than those from controls following 30 min ischaemia. Left ventricular developed pressure (LVDP) was significantly reduced upon early reperfusion (p<0.042) in MLP rats compared to controls. NAC pre-treatment had no effect on LVDP of hearts from control animal hearts but improved the revival of MLP hearts to the same level as controls. DEM treatment did not affect control hearts but significantly reduced recovery of LVDP of MLP hearts during early (p<0.008) and late reperfusion (0.035). Combined NAC and DEM treatment had no effect on LVDP between control and MLP fed offspring. Prenatal protein restriction throughout pregnancy increases the susceptibility of the adult rat heart to suffer a functional deficit following ischaemia-reperfusion injury. Pharmacologically improving antioxidant status prevented this injury. A nutritionally-imbalanced developmental environment may increase susceptibility to coronary heart disease through the programming of myocardial glutathione metabolism.     

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.     

A Maternal High Fat Diet Programmes Endothelial Function and Cardiovascular Status in Adult Male Offspring Independent of Body Weight,Which is Reversed by Maternal Conjugated Linoleic Acid (CLA) Supplementation

Maternal high fat intake during pregnancy and lactation can result in obesity and adverse cardio-metabolic status in offspring independent of postnatal diet. While it is clear that maternal high fat intake can cause hypertension in adult offspring, there is little evidence regarding the role of dietary interventions in terms of reversing these adverse effects. Conjugated linoleic acid (CLA) is an omega 6 fatty acid with beneficial effects in obesity and metabolic status. However, the impact of CLA supplementation in the context of pregnancy disorders and high fat diet-induced developmental programming of offspring cardio-metabolic dysfunction has not been investigated. We have utilised a model of maternal overnutrition to examine the effects of CLA supplementation on programmed endothelial dysfunction during adulthood. Female Sprague-Dawley rats were fed either a purified control diet (CON) or purified control diet supplemented with 1% CLA (of total fat), a purified high fat (HF) diet (45%kcal from fat) and a purified HF diet supplemented with 1% CLA (of total fat) (HFCLA). All dams were fed ad libitum throughout pregnancy and lactation. Offspring were fed a standard chow diet from weaning (day 21) until the end of the study (day 150). Systolic blood pressure (SBP) was measured at day 85 and 130 by tail cuff plethysmography. At day 150, offspring mesenteric vessels were mounted on a pressure myograph and vascular responses to agonist-induced constriction and endothelium-dependent vasodilators were investigated. SBP was increased at day 85 and 130 in HF and HFCLA adult male offspring compared to CON and CLA groups with no effect of CLA supplementation. An overall effect of a maternal HF diet was observed in adult male vessels with a reduced vasoconstrictor response to phenylephrine and blunted vasodilatory response to acetylcholine (ACh). Furthermore, HF and HFCLA offspring displayed a reduction in nitric oxide pathway function and an increased compensatory EDHF function when compared to CON and CLA groups. These data suggest that a maternal HF diet causes a developmental programming of endothelial dysfunction and hypertension in male offspring which can be partially improved by maternal CLA supplementation, independent of offspring body weight.     

Sex differences in postnatal growth and renal development in offspring of rabbit mothers with chronic secondary hypertension

Previously, we demonstrated that adult blood pressure was increased in offspring of rabbit mothers with chronic secondary renal hypertension. Our study identified sex-specific differences in the programming of hypertension, with female, not male, offspring, having increased blood pressure at 30 wk of age. The aim of this study was to characterize the maternal hypertension during pregnancy to determine potential programming stimuli. Further, we examined the impact of chronic maternal hypertension on offspring birth weight, nephron number, and renal noradrenaline content (as an index of renal innervation density). Three groups of mothers and their offspring were studied: two-kidney, one-wrap (2K-1W, n = 9 mothers) hypertensive, two-kidney, two-wrap (2K-2W, n = 8) hypertensive, and a sham-operated group (n = 9). Mean arterial blood pressure was increased by approximately 20 mmHg throughout pregnancy in both hypertensive groups compared with sham mothers (P(G) < 0.001). Plasma renin activity (PRA; P(G) < 0.05) and aldosterone (P(G) < 0.05) levels were increased during gestation in the 2K-1W, but not the 2K-2W mothers. Birth weight was increased by approximately 20% in offspring of both groups of hypertensive mothers (P(T) < 0.001), though this was associated with a reduction in litter size. Renal noradrenaline content was increased ( approximately 40%, P < 0.05) at 5 wk of age in female 2K-1W offspring compared with sham offspring. Glomerular number was not reduced in female offspring of either group of hypertensive mothers; however, glomerular tuft volume was reduced in female 2K-2W offspring (P < 0.05), indicative of a reduction in glomerular filtration surface area. In conclusion, the two models of renal hypertension produced differential effects on the offspring. The impact of a stimulated maternal renin-angiotensin system in the 2K-1W model of hypertension may influence development of the renal sympathetic nerves and contribute to programming of adult hypertension.     

Maternal nutrient restriction during placental growth,programming of fetal adiposity and juvenile blood pressure control

Epidemiological and experimental studies have demonstrated that maternal undernutrition during pregnancy is associated with abnormal placental growth. In sheep, maternal nutrient restriction over the period of rapid placental growth (30-80 days) restricts placentome growth. Then following adequate nutrition up to term (147 days), placental mass is greater in association with a higher total abundance of the predominant placental glucose transporter-1. The resulting lambs are larger at birth, have heavier kidneys with an increased expression of the glucocorticoid-responsive type 1 angiotensin II receptor. Near to term, these fetuses possess more adipose tissue, the endocrine sensitivity of which is markedly enhanced. For example, the abundance of mRNA for 11beta-hydroxysteroid dehydrogenase type 1, which catalyses the conversion of cortisone to bio-active cortisol is increased. This is associated with a higher abundance of both leptin and glucocorticoid receptor mRNA. At 6 months of age, the juvenile offspring of nutrient restricted ewes have lower resting blood pressure that was positively correlated with plasma cortisol concentration, suggesting their blood pressure could be more strongly driven by circulating cortisol. These offspring also exhibited a greater pressor response to vasoconstrictor challenges, but showed no difference in vasodilatory response. At this age, the kidney weight was similar between groups, but the abundance of cytochrome c in kidney mitochondria was enhanced in lambs born to nutrient restricted ewes that could indicate increased mitochondrial activity. Reduced maternal nutrition during the period of rapid placental growth may therefore contribute to hypertension in later life through physiological and vascular adaptations during fetal life.     

An early fish oil-enriched diet reverses biochemical, liver and adipose tissue alterations in male offspring from maternal protein restriction in mice

Fetal programming is linked to adulthood metabolic and chronic diseases. We hypothesized that early fish oil (FO) intake would revert the programming responses in adult offspring. Pregnant mice were fed either standard chow (SC) or a low-protein diet (LP) throughout pregnancy/lactation. At weaning, the following groups were formed: SC and SC-FO, LP and LP-FO, which were fed SC or SC+FO, respectively. The LP offspring are predisposed to becoming fat, hypercholesterolemic and hyperglycemic. In addition, during adulthood, they become hypertensive with hepatic steatosis and have a high level of sterol regulatory element binding protein (SREBP-1). However, LP offspring that were fed an FO-enriched diet have decreased body mass (BM) gain and lower final BM. In addition, with this diet, these mice have improved lipid metabolism with a decrease in total cholesterol (TC) and triacylglyceride (TG) levels, reduced fat pad masses and reduced adipocyte size. Furthermore, these LP offspring show reduced liver structural damage of alanine aminotransferase (ALT), liver steatosis with low SREBP-1 protein expression and high peroxisome proliferator activity receptor-alpha expression, and improvement of blood pressure (BP) and tumor necrosis factor (TNF)-alpha level. Early fish oil intake has beneficial effects on the programming responses that control body fat pad, glucose and lipid metabolism, and liver and adipose tissue structure in adult programmed offspring.