Restriction of maternal protein intake during rat pregnancy produces offspring that are hypertensive in adulthood, but the mechanisms are not well understood. Our purpose was to determine whether this adult hypertension could be programmed during development by suppression of the fetal/newborn reninangiotensin system (RAS) and a consequent reduction in nephron number. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Birth weight was reduced by 13% (p Ͻ 0.0005), and the kidney/body weight ratio was reduced in LP pups. Renal renin mRNA levels were significantly reduced in newborn LP pups; renal renin concentration and renin immunostaining were suppressed. Renal tissue angiotensin II levels were also suppressed in newborn LP (0.079 Ϯ 0.002 ng/mg, LP versus 0.146 Ϯ 0.016 ng/mg, NP, p Ͻ 0.01). Mean arterial pressure in conscious, chronically instrumented adult offspring (21 wk) was higher in LP (135 Ϯ 1 mm Hg, LP versus 126 Ϯ 1 mm Hg, NP, p Ͻ 0.00007), and GFR normalized to kidney weight was reduced in LP (p Ͻ 0.04). The number of glomeruli per kidney was lower in adult LP offspring (21,567 Ϯ 1,694, LP versus 28,917 Ϯ 2,342, NP, p Ͻ 0.03), and individual glomerular volume was higher (1.81 Ϯ 0.16 10 6 m 3 , LP versus 1.11 Ϯ 0.10 10 6 m 3 , NP, p Ͻ 0.005); the total volume of all glomeruli per kidney was not significantly different. Thus, perinatal protein restriction in the rat suppresses the newborn intrarenal RAS and leads to a reduced number of glomeruli, glomerular enlargement, and hypertension in the adult. Abbreviations RAS, renin-angiotensin system ERPF, effective renal plasma flow NP, normal protein (19%) diet LP, low-protein (8.5%) diet ANGII, angiotensin II PAH, para-amino hippurate A decade ago, Barker et al. first reported an inverse relationship between birth weight and death from cardiovascular disease in adulthood (1). Subsequently, a number of epidemiologic studies in different parts of the world have found a relationship between early growth patterns and the risk of cardiovascular disease in adulthood (2-8). Although these findings remain somewhat controversial (9), the majority of evidence indicates that even within the "normal" range of birth weights, babies that are born smaller have a higher risk of death from cardiovascular disease when they reach adulthood. This indicates that some factor or factors in the perinatal environment, probably related at least in part to maternal nutrition, can "program" the individual for increased cardiovascular risk later in life. However, the precise physiologic and molecular mechanisms by which this programming occurs are unknown.Recently, a rat model of perinatal protein restriction has been identified that has several features in common with the observations in humans, suggesting that this may be a good animal model of the human condition. In particular, offspring ABSTRACT460

Programming of adult blood pressure by maternal protein restriction: Role of nephrogenesis.Background. Modest maternal protein restriction leads to hypertension and a reduced number of glomeruli in adult male but not female offspring. This study determined whether a more severe protein restriction has equivalent effects on male and female rat offspring, and examined the role of nephrogenesis in this programming.Methods. Sprague-Dawley rats were fed a protein-restricted (5% protein) diet throughout (LLP), or during the first (LLP/NP) or second (NP/LLP) half of pregnancy. Controls ate a normal diet (NP, 19% protein). Adult offspring were chronically instrumented at 22 weeks; glomerular number and volume were estimated using stereologic techniques.Results. Mean arterial pressures in male offspring were significantly higher in LLP (136 ± 2 mm Hg) or NP/LLP (137 ± 2 mm Hg) than in LLP/NP (125 ± 1 mm Hg) or NP (125 ± 2 mm Hg). Moreover, the hypertension was salt-sensitive (increase of 16 ± 4 mm Hg in LLP on a high Na + diet compared to 2 ± 2 mm Hg in NP). Glomerular number (per kidney) was reduced (15,400 ± 2,411 in LLP vs. 27,208 ± 1,534 in NP) but average individual glomerular volume was not different (1.98 ± 0.18 10 6 l 3 in LLP vs. 2.01 ± 0.14 10 6 l 3 in NP). Female offspring showed qualitatively similar results.Conclusion. Severe maternal dietary protein restriction reduces glomerular number and programs for salt-sensitive adult hypertension in both female and male offspring. The window of sensitivity of adult blood pressure to prenatal protein restriction falls within the period of nephrogenesis in the rat. These data are consistent with the hypothesis that maternal protein restriction causes adult hypertension in the offspring through impairment of renal development.Epidemiologic evidence indicates that babies that are born smaller or grow more slowly during the first year of life have an increased risk for adult diseases, including heart disease and hypertension, than do larger babies [1][2][3][4][5][6][7][8]. This indicates that factors in the prenatal and early postnatal environment, that influence growth, can cause permanent changes in the morphology and physiology of specific organ systems, thus "programming" the individual for increased risk of disease later in life. One such factor that is known to cause this programming is maternal undernutrition. In the rat, maternal dietary protein restriction during pregnancy leads to hypertension in adult offspring [9][10][11], but the precise physiologic mechanisms by which this occurs remain controversial. We have previously hypothesized that maternal protein restriction causes suppression of the fetal/newborn intrarenal renin-angiotensin system (RAS), and thus impaired renal development, leading to permanent alterations in kidney structure and function, including a reduced number of nephrons, resulting in hypertension. In support of this postulate, we found that renal renin gene expression, renin protein, and angiotensin II levels are suppressed in newborn male o...

restriction in the rat leads to hypertension in adult male offspring. The purpose of this study was to determine whether female rats are resistant to developing the increased blood pressure seen in male rats after maternal protein restriction. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Renal renin protein and ANG II levels were reduced by 50 -65% in male LP compared with NP pups, but were not suppressed in female LP compared with female NP. Mean arterial pressure in conscious, chronically instrumented adult female offspring (22 wk

ANG II is known to be important in normal renal development, but the long-term consequences of a suppressed renin-angiotensin system (RAS) during the developmental period are not completely understood. This study tested the hypothesis that the RAS in the developing animal is important in long-term regulation of renal function and arterial pressure. Newborn Sprague-Dawley rat pups were given the ANG II AT1 receptor antagonist losartan (25 mg ⋅ kg−1 ⋅ day−1sc) for the first 12 days of postnatal life (Los). Body weights at weaning (22 days) were significantly reduced in Los (53.4 ± 3.2 vs. 64.5 ± 3.6 g in controls); however, at the time of study (∼22 wk), body weights and the kidney-to-body weight ratios were not different. In chronically instrumented conscious animals, glomerular filtration rate and effective renal plasma flow were reduced by 27 and 20%, respectively, in Los; the filtration fraction was not different. Maximal urine concentrating ability was also reduced in Los (1,351 ± 45 vs. 2,393 ± 52 mosmol/kg in controls). Mean arterial pressure was significantly higher in Los (134 ± 3 vs. 120 ± 1 mmHg). The number of glomeruli per kidney was reduced by 42% in Los, but the total glomerular volume was unchanged. Thus perinatal blockade of ANG II AT1 receptors results in fewer but enlarged glomeruli, reduced renal function, and an increased arterial pressure in adulthood. These data indicate that perinatal ANG II, acting via AT1 receptors, plays an important role in renal development and long-term control of renal function and arterial pressure. Physiological conditions that cause suppression of the RAS in the developing animal may have long-term consequences for renal function and blood pressure.

No abstract

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.

No abstract

The present study was designed to determine whether adult hypertension caused by a reduced number of nephrons from birth is due to preceding glomerular damage. Newborn male Sprague-Dawley rat pups were uninephrectomized during the first 24 hours after birth (UNX rats). At 20 weeks of age, chronically instrumented UNX animals were hypertensive on a normal-sodium (0.20%) diet compared with sham-operated controls (1422 versus 1242 mm Hg in controls). Body weights and the total kidney-to-body weight ratio were not significantly different in adult UNX animals compared with controls. Glomerular filtration rate (GFR) was reduced by 49% in UNX rats (1.850.24 versus 3.650.22 mL/min). Urine protein excretions were higher in UNX rats (202 versus 71 mg/d in controls). On a high-sodium (3.15%) diet, arterial pressure increased more in UNX than in controls (289 versus 31 mm Hg). In contrast, in animals studied at 8 weeks of age, GFR was only reduced by 26% in UNX animals (2.020.06 versus 2.730.07 mL/min). Their hypertension (1252 versus 1172 mm Hg) was also salt sensitive (increase on high-sodium diet of 3511 versus 82 mm Hg in controls) but was not associated with proteinuria or histological signs of glomerular disease. Number of glomeruli per kidney in UNX animals was not different from controls, but individual glomerular volume increased by 41%. Thus, surgical removal of 50% of the nephrons, when done during development, causes reduced renal function and salt-sensitive hypertension in adulthood. Hypertension is present earlier in life than signs of glomerular disease, which suggests that hypertension is a major contributor to rather than primarily resulting from onset of renal disease. (Hypertension. 2001;38:337-342.) Key Words: kidney glomerular filtration rate renal blood flow sodium development gender R esearch has established that the kidney plays a dominant role in long-term regulation of arterial pressure and, therefore, in the development of hypertension. 1 Brenner and colleagues 2 have postulated that the risk of developing essential hypertension in adulthood is inversely related to nephron endowment at birth. We have recently shown in female rats that surgical reduction in the number of nephrons (uninephrectomy) when done during development, results in hypertension in adulthood 3 ; these results support the postulate of Brenner et al. However, other investigators have shown in male rats that uninephrectomy at 10 days postnatal age results in signs of glomerular damage relatively early in life. 4 Because hypertension can be either a cause or a result of glomerular disease (or both), it is important to establish the time course of the occurrence of these 2 phenomena. The present study was designed to test the hypothesis that unine-phrectomy during development results in hypertension before glomerular damage occurs. Methods Female Sprague-Dawley rats (Simonsen) weighing 250 to 300 g each were bred at Oregon Health Sciences University and maintained on a normal-sodium (0.20%) diet (Purina 5755) ad libitum throughout p...