Prenatal Programming Of Hypertension Research Articles

Sex differences in prenatal programming of hypertension by dexamethasone.

Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.

ВЛИЯНИЕ ПЕРИНАТАЛЬНЫХ ФАКТОРОВ И РИСК АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИИ У ДЕТЕЙ (ЧАСТЬ 2)

The article presents data about maternal and prenatal influences lead to «programming» of arterial hypertension (AH) in the child's later life. A special group that is threatened by the development of AH at an older age is premature children and children with intrauterine development delay due to a small number of nephrons and the launch of prenatal programming of hypertension. The state of the mother's health before conception, as well as the use of assisted reproductive technologies, despite a normal pregnancy in general and the birth of a healthy newborn can provoke the development of hypertension in childhood.

Up-regulation of renal renin–angiotensin system and inflammatory mechanisms in the prenatal programming by low-protein diet: beneficial effect of the post-weaning losartan treatment

Previous studies have shown that the renin-angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. The aim of this study was to investigate the effects of a maternal low-protein diet on proinflammatory cytokines, reactive oxygen species and RAS components in kidney samples isolated from adult male offspring. We hypothesized that post-weaning losartan treatment would have beneficial effects on RAS activity and inflammatory and oxidative stress markers in these animals. Pregnant Sprague-Dawley rats were fed with a control (20% casein) or low-protein diet (LP) (6% casein) throughout gestation. After weaning, the LP pups were randomly assigned to LP and LP-losartan groups (AT1 receptor blockade: 10 mg/kg/day until 20 weeks of age). At 20 weeks of age, blood pressure levels were higher and renal RAS was activated in the LP group. We also observed several adverse effects in the kidneys of the LP group, including a higher number of CD3, CD68 and proliferating cell nuclear antigen-positive cells and higher levels of collagen and reactive oxygen species in the kidney. Further, our results revealed that post-weaning losartan treatment completely abolished immune cell infiltration and intrarenal RAS activation in the kidneys of LP rats. The prevention of augmentation of angiotensin (Ang II) concentration abolished inflammatory and fibrotic events, indicating that Ang II via the AT1 receptor is essential for pathological initiation. Our results suggest that the prenatal programming of hypertension is dependent on the up-regulation of local RAS and presence of immune cells in the kidney.

Role of renal sympathetic nerve activity in prenatal programming of hypertension.

Prenatal insults, such as maternal dietary protein deprivation and uteroplacental insufficiency, lead to small for gestational age (SGA) neonates. Epidemiological studies from many different parts of the world have shown that SGA neonates are at increased risk for hypertension and early death from cardiovascular disease as adults. Animal models, including prenatal administration of dexamethasone, uterine artery ligation and maternal dietary protein restriction, result in SGA neonates with fewer nephrons than controls. These models are discussed in this educational review, which provides evidence that prenatal insults lead to altered sodium transport in multiple nephron segments. The factors that could result in increased sodium transport are discussed, focusing on new information that there is increased renal sympathetic nerve activity that may be responsible for augmented renal tubular sodium transport. Renal denervation abrogates the hypertension in programmed rats but has no effect on control rats. Other potential factors that could cause hypertension in programmed rats, such as the renin-angiotensin system, are also discussed.

Effect of Postnatal Maternal Protein Intake on Prenatal Programming of Hypertension

This study examined whether postnatal maternal dietary protein deprivation during the time of nursing can program hypertension when the offspring are studied as adults. Rats were fed either a 6% or 20% protein diet during the second half of pregnancy and continued on the same diet while rats were nursing their pups. The neonates of all of the rats were cross-fostered to a different mother and studied as adults. Adult rats that had a normal prenatal environment but were reared by mothers fed a low-protein diet until weaning (20%-6%) were hypertensive, had a higher renal Na(+)-K(+)-2Cl(-) cotransporter (NKCC2) and Na(+)-Cl(-) cotransporter (NCC) protein abundance yet a comparable number of glomeruli, and had higher plasma renin and angiotensin II levels compared to control (20%-20%). Rats whose mothers were fed a 6% protein diet and cross-fostered to a different rat fed a 6% protein diet until weaning (6%-6%) were hypertensive, had elevated plasma renin and angiotensin II levels, and had a reduction in nephron number but had NKCC2 and NCC levels comparable to 20% to 20% offspring. The 6% to 20% had blood pressure and glomerular numbers comparable to 20% to 20% rats. The hypertension resulting from prenatal dietary protein deprivation can be normalized by improving the postnatal environment. Combined prenatal and postnatal maternal dietary protein deprivation and maternal dietary protein deprivation while nursing alone (20%-6%) results in hypertension, but the mechanism for the hypertension in these groups is different.

Activation of the sympathetic nervous system, is it key to the developmental origins of enhanced cardiovascular risk?

the barker hypothesis or the theory of fetal programming proposes that undernutrition during fetal life slows fetal growth programming an increase in risk factors for cardiovascular disease ([10][1]). Numerous experimental models of undernutrition induced by protein restriction during gestation or

Prenatal Programming of Hypertension Induces Sympathetic Overactivity in Response to Physical Stress

Small-for-gestational-age infants are known to develop hypertension in adulthood. This prenatal programming of hypertension (PPH) can result from several insults including maternal dietary protein deprivation, uteroplacental insufficiency, and prenatal administration of glucocorticoids. The mechanisms underlying the development of hypertension remain unclear although the sympathetic nervous system has been indirectly implicated. This study was designed to directly measure renal sympathetic nerve activity both at rest and during physical stress in an animal model of PPH. The adult male offspring of rats fed either a 6% (PPH) or 20% protein diet (control) were investigated. Conscious systolic blood pressure measured by tail cuff was significantly higher in PPH compared with control (140 ± 3 versus 128 ± 3 mm Hg; P<0.05). Baseline mean arterial pressure, heart rate, and renal sympathetic activity were not different between groups during isoflurane anesthesia or after decerebration. Physical stress was induced in decerebrate animals by activating the exercise pressor reflex during static muscle contraction. Stimulation of the exercise pressor reflex evoked significantly larger changes from baseline in mean arterial pressure (40 ± 7 versus 20 ± 4 mm Hg; P<0.05), heart rate (19 ± 3 versus 5 ± 1 bpm; P<0.05), and renal sympathetic activity (198 ± 29% versus 68 ± 14%; P<0.05) in PPH as compared with control. The data demonstrate that the sympathetic response to physical stress is markedly exaggerated in PPH and may play a significant role in the development of hypertension in adults born small for gestational age.

Prenatal Programming of Hypertension

See related article, pp 180–186 The hemodynamic response to physical stress has been studied over the past decade, and it is considered an indicator of cardiovascular risk.1 The blood pressure response during acute exercise includes participation of the sympathetic nervous system, involving brain centers and peripheral reflexes.1 The sympathetic nervous system has a critical role in the regulation of blood pressure and in the cause of hypertension. Several reports from human and experimental models proposed that increased sympathetic activity is linked to hypertension and cardiovascular and renal diseases. Currently, there are 2 phase III clinical trials testing mechanical manipulations of the sympathetic nervous system as a treatment for hypertension. The SYMPLICITY HTN-3 Study is evaluating the safety and efficacy of renal denervation as a treatment for hypertension.2 The XR-1 Verification Study is assessing the safety and efficacy of carotid baroreflex activators in patients with drug-resistant hypertension.3 These clinical trials are the results of decades of research targeting the involvement of the sympathetic nervous system in the cause of hypertension. However, few studies are investigating the causes of dysfunction in this important regulatory system. What triggers the increases in sympathetic nervous system activity is still unclear. The effects of adverse environment, such as poor nutrition …

Prenatal Programming of Hypertension in the Rat: Effect of Postnatal Rearing

Background/Aims: Dietary protein deprivation during pregnancy causes hypertension in offspring when they become adults. This study examined if postnatal rearing had an effect on blood pressure and glomerular number in male rats whose mothers were fed either a control diet or a low protein diet. Methods: Neonates were cross fostered at 1 day of age to a different mother. After birth, all nursing and weaned rats were fed a control diet. Blood pressure and glomerular number were measured in adult offspring. Results: Control rats cross fostered to another control mother had a lower blood pressure than low protein rats cross fostered to another low protein mother (133 ± 4 vs. 151 ± 4 mm Hg, p < 0.05) and a greater number of glomeruli (28,388 ± 989 vs. 25,045 ± 851, p < 0.05). Fostering pups from the 20% group to mothers that were fed a 6% diet during pregnancy did not cause hypertension or a reduction in the number of glomeruli. However, fostering the 6% group on to mothers that were fed a 20% protein diet during pregnancy resulted in normalization of the blood pressure and number of glomeruli. Conclusion: The hypertension and reduced glomerular number resulting from prenatal dietary protein deprivation can be normalized by improving the postnatal environment.

Evidence That Prenatal Programming of Hypertension by Dietary Protein Deprivation Is Mediated by Fetal Glucocorticoid Exposure

Prenatal programming by maternal dietary protein deprivation and prenatal dexamethasone result in a reduction in nephron number and hypertension when the offspring are studied as adults. To determine whether prenatal dietary protein deprivation results in a reduction in nephron number and hypertension in offspring by exposure to maternal glucocorticoids, we administered metyrapone to rats fed either a 6% or 20% protein diet to inhibit glucocorticoid production and compared the offspring to rats that were the product of mothers fed either a 6% or 20% protein diet during the last half of pregnancy. Male offspring from the 6% group had elevated systolic blood pressure (149 ± 2 vs. 130 ± 5 mm Hg, P < 0.05) and a reduction in glomeruli compared to the 20% group (22,111 ± 627 vs. 29,666 ± 654 glomeruli/kidney, P < 0.001). Maternal metyrapone administration did not affect the blood pressure in the 20% group but ameliorated the increase in blood pressure in the 6% male group to values comparable to the 20% control group (138 ± 6 vs. 130 ± 5 mm Hg). Male offspring of the 6% group that received metyrapone had an increase in the number of glomeruli compared to the vehicle-treated 6% group (26,780 ± 377 vs. 22,111 ± 627 glomeruli/kidney, P < 0.001), but less glomeruli compared to the 20% protein control group (26,780 ± 377 vs. 29,666 ± 654 glomeruli/kidney, P = 0.01). The reduction in nephron number and hypertension induced by maternal protein deprivation in male offspring is ameliorated by inhibition of glucocorticoid production.

Effect of Prenatal Dexamethasone on Postnatal Serum and Urinary Angiotensin II Levels

Prenatal programming of hypertension has been described in humans and in animal models that receive a prenatal insult, but the mechanism for the increase in blood pressure remains elusive. In male rats whose mothers received dexamethasone between days 15 and 18 of gestation systemic and urinary levels of angiotensin II were measured to determine whether angiotensin II was a potential factor for the generation (4 weeks of age) or maintenance (8 weeks of age) of hypertension. A group 4- and 8-week-old male rats that were the product of a pregnancy where the mother received prenatal dexamethasone between days 15 and 18 of gestation had comparable plasma renin and angiotensin II levels to the offspring of vehicle-treated controls. Renal angiotensin II levels were not different at 4 and 8 weeks of age between the controls and the prenatal dexamethasone group. Urine angiotensin II/Creatinine levels, a reflection of filtered and renally generated and secreted angiotensin II, were higher at both 4 and 8 weeks of age in male rats that received prenatal dexamethasone compared to controls. The high-urine angiotensin II levels in prehypertensive and hypertensive rats that were the product of mothers that received dexamethasone compared to vehicle suggest that luminal angiotensin II may play a role in the generation and maintenance of hypertension in this model of prenatal programming.

Epigenetic changes in gene expression: focus on “The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction”

the term epigenetics was first coined in 1942 by Waddington ([20][1]) to describe the interaction of genes with their environment during development that gives rise to a phenotype. Today, the term epigenetics is used when describing a phenotype that occurs in a manner outside conventional genetic

Programming of hypertension: the nervous kidney

two decades after Barker and coworkers ([2][1]) described an inverse epidemiological relationship between birth weight and risk of adult cardiovascular morbidity, including hypertension, the pathophysiology of prenatally programmed hypertension remains incompletely understood. Experimental models

Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance

Prenatal glucocorticoids are often administered to pregnant women to accelerate pulmonary maturation. We have demonstrated that administration of dexamethasone during specific periods of pregnancy in the rat causes hypertension in the offspring when they are studied as adults. The purpose of the present study was to determine whether the hypertension due to prenatal dexamethasone was mediated by renal nerves. We administered dexamethasone to rats daily for 4 days between days 15 and 18 of gestation. Rats underwent bilateral renal denervation or sham operation at 6 wk of age, and blood pressure was measured at 8 wk of age. Prenatal dexamethasone in the sham operation group resulted in an increase in blood pressure compared with vehicle-treated sham controls (134 +/- 3 vs. 145 +/- 3 mmHg, P < 0.05). Renal denervation did not affect blood pressure significantly in the prenatal vehicle-treated control group but resulted in normalization in blood pressure in the prenatal dexamethasone group and (130 +/- 3 and 128 +/- 5 mmHg, respectively). Prenatal dexamethasone increased type 3 Na+/H+ exchanger (NHE3), Na+K+-2Cl(-) cotransporter (NKCC2), and Na+-Cl(-) cotransporter (NCC), but not alpha-, beta-, and gamma-epithelial Na+ channel (ENaC) protein abundance compared with controls. The increase in NHE3, NKCC2, and NCC protein abundance by prenatal dexamethasone was not seen in 8-wk-old rats 2 wk after renal denervation. Renal denervation did not affect NHE3, NKCC2, and NCC protein abundance in prenatal vehicle-treated animals. This study is consistent with renal nerves playing a role in mediating the hypertension by prenatal programming by dexamethasone.

Developmental Programming Through Epigenetic Changes

See related article, pages 520–526 The last decade has seen an exponential number of scientific articles addressing the concept of fetal programming of adult onset diseases. Though it has long been known (as it is probably part of common knowledge in human history) that the environment and life events during the fetal period impact on the child’s development, the notion that intrauterine life can also impact on adult health and on the incidence of late onset diseases such as hypertension and type II diabetes is relatively more recent. In 1964, Rose reported the association of ischemic heart disease and infant mortality within the same families (reviewed by1). Then Forsdahl in 1977 showed that incidence of arteriosclerotic heart disease in a certain age group could be correlated with the infant mortality rate of that same population.1 Interest in these types of association rose dramatically following Professor Barker and collaborators’ extensive observations of a well documented population in England and Wales. The meticulous work of home health visitors in the early 20th century, which noted every child weight and length at birth and throughout the first year of life as well as other observations of the mother health and living milieu, generated data which clearly demonstrated an inverse relationship between birthweight and adult incidence of cardiovascular related mortality and morbidities as well as type II diabetes.1 We will focus here on hypertension and related complications. The association between birthweight and adult blood pressure was demonstrated in many parts of the world, in industrialized as well as in more developing countries, in both men and women.1 The association is first noted in early childhood (but not at birth) and seems to increase with age. Despite the significant number of studies published, which have examined to date tens …

Maternal glucocorticoids and prenatal programming of hypertension

Maternal glucocorticoids have been postulated to play an important role in prenatal programming for adult hypertension in the offspring. However, we have shown previously that offspring hypertension caused by maternal dexamethasone subcutaneous administration at 100 microg x kg(-1) x day(-1) can be accounted for by the corresponding reduction in food intake that these mothers experience. The present studies were designed to determine whether there is a lower dose of dexamethasone that does not reduce maternal food intake yet still causes hypertension in the adult offspring. Pregnant rats were treated with subcutaneous dexamethasone at 50 (D50) or 25 (D25) microg x kg(-1) x day(-1) on days 15-20 of pregnancy. An additional group was untreated or received vehicle injections (control). D25 and D50 dams reduced their food intake by 17% during and after treatment and gained 31% less weight than control over the course of gestation. In adulthood ( approximately 21 wk), chronically instrumented male offspring of D50 and D25 had normal blood pressures (D50: 131 +/- 2 mmHg and D25: 127 +/- 3 mmHg vs. 127 +/- 2 mmHg in control). Qualitatively similar results were found in female offspring. Thus neither dexamethasone per se at these doses nor the accompanying modest reductions in maternal food intake and weight gain have blood pressure programming effects. As far as has been tested, there does not appear to be a dose of dexamethasone that, given over this time period in the rat, programs offspring hypertension without reducing maternal food intake and weight gain. These data do not support the hypothesis that maternal glucocorticoids program offspring hypertension directly.

Prenatal programming of hypertension in common marmoset Mmnkeys by dexamethasone

Prenatal programming of hypertension in common marmoset Mmnkeys by dexamethasone

Prenatal Programming of Hypertension

As discussed elsewhere in this issue, beginning with David Barker’s insight and original observations leading to the Fetal Origins of Adult Disease hypothesis ([1][1]), epidemiologic studies have strongly suggested that an adverse intrauterine environment may lead to adult hypertension ([2][2]–[

Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension

Adult hypertension may be programmed by the prenatal environment in humans and in experimental animals. The potential role of the intrarenal renin-angiotensin system (RAS) in prenatally programmed hypertension was investigated. Hypertension in rat offspring was induced by maternal protein restriction during pregnancy. The offspring were studied on day 1 of life and immediately preceding the development of hypertension on day 28. ANG I and II contents were determined by radioimmunoassy. Angiotensin receptor protein and mRNA levels were quantified by immunoblotting and real-time RT-PCR, respectively. Plasma and kidney ANG I and II were unchanged in the offspring from low-protein pregnancies (LP). ANG II type 1 receptor (AT(1)R) protein abundance was low in the newborn LP kidney (P < 0.05) but rose above control values by 28 days of age (P < 0.05); the rise was associated with an increase in AT(1)R subtype A (P < 0.01), but not subtype B, mRNA level. ANG II type 2 receptor protein expression was decreased on day 1 (P < 0.05) and increased on day 28 (P < 0.05) in LP kidneys. The results show that prenatal programming of hypertension is associated with an abnormal pattern of intrarenal RAS ontogeny that may play a pathogenetic role, for instance, by constitutively altering renal hemodynamics or Na reabsorption.

Antihypertensive treatment in early postnatal life modulates prenatal dietary influences upon blood pressure in the rat

Epidemiological evidence from diverse human populations, supported by experimental evidence from animal models, suggests that maternal nutrition during pregnancy is an important fetal programming influence upon cardiovascular disease. Experiments with a low-protein-diet model of rat pregnancy suggest a role for the renin-angiotensin system in the programming mechanism, since fetal undernutrition permanently elevates pulmonary and plasma angiotensin-converting enzyme activity. Long-term beneficial effects of captopril on blood pressure in this model require further investigation in order to clarify the role of angiotensin II. Pregnant rats were fed a control diet containing 18% (w/w) casein as the protein source or a low-protein diet containing 9% (w/w) casein. Between the ages of 2 and 4 weeks postnatally, mothers and their pups were treated with losartan or nifedipine. All pups in the study had blood pressure determined at 4 and 12 weeks of age using a tail cuff. Animals exposed to the low-protein diet in utero and not subjected to drug treatment had elevated blood pressure relative to control rats (mean increase of 27 mmHg; P<0.001). Treatment of rats exposed to the control diet in utero with either nifedipine or losartan between 2 and 4 weeks of age did not alter their blood pressure. Nifedipine had no effect upon the blood pressure of low-protein-exposed pups, but losartan prevented the blood pressure elevation in these animals. Between 4 and 12 weeks of age, blood pressure increased significantly in all groups (P<0.001). The pattern of blood pressure among the groups was identical to that observed at 4 weeks, suggesting that the observed early effects of losartan would be maintained into adult life. The data are consistent with the hypothesis that angiotensin II plays a major role in the prenatal programming of hypertension. The action of angiotensin II at the AT(1) receptor between 2 and 4 weeks of age may be critically up-regulated by fetal factors, including exposure to glucocorticoids of maternal origin.