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• W1972339030 abstract "Impaired growth in utero predicts a low nephron number and high blood pressure later in life as does slowed or accelerated growth after a normal birth weight. We measured the effects of early postnatal growth restriction, with or without prenatal growth restriction, on blood pressure and nephron number in male rat offspring. Bilateral uterine artery and vein ligation were performed to induce uteroplacental insufficiency (Restricted) on day 18 of pregnancy. Postnatal growth restriction was induced in a subset of sham operated control animals by reducing the number of pups at birth to that of the Restricted group (Reduced Litter). Compared to Controls, Restricted pups were born smaller while Reduced Litter pups weighed less by postnatal day 3 and both groups remained lighter throughout lactation. By 10 weeks of age all animals were of similar weight but the Reduced Litter rats had elevated blood pressure. At 22 weeks, Restricted but not Reduced Litter offspring were smaller and the blood pressure was increased in both groups. Restricted and Reduced Litter groups had fewer glomeruli and greater left ventricular mass than Controls. These results suggest that restriction of both perinatal and early postnatal growth increase blood pressure in male offspring. This study also demonstrates that the early postnatal period is a critical time for nephron endowment in the rat. Impaired growth in utero predicts a low nephron number and high blood pressure later in life as does slowed or accelerated growth after a normal birth weight. We measured the effects of early postnatal growth restriction, with or without prenatal growth restriction, on blood pressure and nephron number in male rat offspring. Bilateral uterine artery and vein ligation were performed to induce uteroplacental insufficiency (Restricted) on day 18 of pregnancy. Postnatal growth restriction was induced in a subset of sham operated control animals by reducing the number of pups at birth to that of the Restricted group (Reduced Litter). Compared to Controls, Restricted pups were born smaller while Reduced Litter pups weighed less by postnatal day 3 and both groups remained lighter throughout lactation. By 10 weeks of age all animals were of similar weight but the Reduced Litter rats had elevated blood pressure. At 22 weeks, Restricted but not Reduced Litter offspring were smaller and the blood pressure was increased in both groups. Restricted and Reduced Litter groups had fewer glomeruli and greater left ventricular mass than Controls. These results suggest that restriction of both perinatal and early postnatal growth increase blood pressure in male offspring. This study also demonstrates that the early postnatal period is a critical time for nephron endowment in the rat. Poor intrauterine growth results in small for gestational age babies and low birth weight predicts an increased risk of developing many adult onset diseases, including hypertension.1.Barker D.J.P. Osmond C. Golding J. et al.Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease.BMJ. 1989; 298: 564-567Crossref PubMed Scopus (1714) Google Scholar It is thought that the fetus, upon exposure to a suboptimal intrauterine environment, makes adaptations, which increase short-term survival. These adaptations impact on normal growth and functional development increasing predisposition to later disease.2.Gluckman P. Hanson M.A. Living with the past: evolution, development, and patterns of disease.Science. 2004; 305: 1733-1736Crossref PubMed Scopus (1311) Google Scholar Growth in the early postnatal period has also been implicated to independently affect later health and result in disease development.3.Eriksson J.G. Tuomilehto J. Winter P.D. et al.Catch-up growth in childhood and death from coronary heart disease: longitudinal study.BMJ. 1999; 318: 427-431Crossref PubMed Scopus (897) Google Scholar,4.Singhal A. Cole T.J. Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials.Lancet. 2001; 357: 413-419Abstract Full Text Full Text PDF PubMed Scopus (457) Google Scholar Accelerated growth in early infancy has been shown to be associated with the later development of coronary artery disease5.Eriksson J.G. Forsén T. Tuomilehto J. et al.Early growth and coronary heart disease in later life: longitudinal study.BMJ. 2001; 322: 948-953Crossref Google Scholar and type II diabetes,6.Eriksson J.G. Forsen T. Tuomilehto J. et al.Early adiposity rebound in childhood and risk of type 2 diabetes in adult life.Diabetologia. 2003; 46: 190-194PubMed Google Scholar although other studies suggest that slowed postnatal growth, especially during the first year, can lead to increased risk of coronary heart disease7.Forsen T.J. Eriksson J.G. Osmond C. et al.The infant growth of boys who later develop coronary heart disease.Ann Med. 2004; 36: 389-392Crossref PubMed Scopus (45) Google Scholar and insulin resistance.8.Eriksson J.G. Osmond C. Kajantie E. et al.Patterns of growth among children who later develop type 2 diabetes or its risk factors.Diabetologia. 2006; 49: 2853-2858Crossref PubMed Scopus (198) Google Scholar Together, these studies suggest that factors that affect prenatal and/or postnatal growth, including nutrition, are important in determining later cardiovascular and metabolic health. In animal studies, maternal dietary manipulations (low protein or calorie restriction during pregnancy) restrict fetal growth and produce offspring that have a reduced nephron number9.Moritz K.M. Dodic M. Wintour E.M. Kidney development and the fetal programming of adult disease.BioEssays. 2003; 25: 212-220Crossref PubMed Scopus (106) Google Scholar and develop hypertension as adults.10.Langley-Evans S.C. Welham S.J. Jackson A.A. Fetal exposure to a maternal low protein diet impairs nephrogenesis and promotes hypertension in the rat.Life Sci. 1999; 64: 965-974Crossref PubMed Scopus (433) Google Scholar,11.Woods L.L. Weeks D.A. Rasch R. Programming of adult blood pressure by maternal protein restriction: role of nephrogenesis.Kidney Int. 2004; 65: 1339-1348Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar Of particular concern is that a congenital nephron deficit has been implicated as a mechanism through which a prenatal perturbation may result in later hypertension.12.Moritz K.M. Boon W.M. Wintour E.M. Glucocorticoid programming of adult disease.Cell Tissue Res. 2005; 322: 81-88Crossref PubMed Scopus (56) Google Scholar However, previous studies have not assessed the effects of an impaired postnatal lactational environment, a period when nephrogenesis continues in the rodent. Of interest is that a pregnancy-induced lactation deficit may persist even when the mother is returned to a normal diet at birth. Although it is evident that offspring undergo variable postnatal growth following maternal nutritional modulation, the role of this in the development of later hypertension has not been studied extensively. In Western society, much of the fetal growth restriction that occurs reflects placental insufficiency and impaired uteroplacental blood flow. Uteroplacental insufficiency and growth restriction, either by bilateral uterine artery and vein ligation13.Alexander B.T. Fetal programming of hypertension.Am J Physiol. 2006; 290: R1-R10Crossref PubMed Scopus (138) Google Scholar,14.Wlodek M.E. Mibus A.L. Tan A. et al.Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.J Am Soc Nephrol. 2007; 18: 1688-1696Crossref PubMed Scopus (166) Google Scholar or aortic clip,15.Jansson T. Lambert G.W. Effect of intrauterine growth restriction on blood pressure, glucose tolerance and sympathetic nervous system activity in the rat at 3–4 months of age.J Hypertens. 1999; 17: 1239-1248Crossref PubMed Scopus (137) Google Scholar,16.Alexander B.T. Placental insufficiency leads to development of hypertension in growth-restricted offspring.Hypertension. 2003; 41: 457-462Crossref PubMed Scopus (216) Google Scholar,17.Lane R.H. Chandorkar A.K. Flozak A.S. et al.Intrauterine growth retardation alters mitochondrial gene expression and function in fetal and juvenile rat skeletal muscle.Pediatr Res. 1998; 43: 563-570Crossref PubMed Scopus (72) Google Scholar,18.Wlodek M.E. Westcott K.T. O'Dowd R. et al.Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP.Am J Physiol. 2005; 288: R1620-R1627Crossref PubMed Scopus (80) Google Scholar have been experimentally induced in several species, including the rat. We have utilized the bilateral uterine vessel ligation model to examine fetal growth and development.14.Wlodek M.E. Mibus A.L. Tan A. et al.Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.J Am Soc Nephrol. 2007; 18: 1688-1696Crossref PubMed Scopus (166) Google Scholar,18.Wlodek M.E. Westcott K.T. O'Dowd R. et al.Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP.Am J Physiol. 2005; 288: R1620-R1627Crossref PubMed Scopus (80) Google Scholar,19.O'Dowd R. Kent J.C. Moseley J.M. et al.The effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.Am J Physiol. 2008; 294: R539-R548Crossref PubMed Scopus (76) Google Scholar Although this model has previously been thought to affect intrauterine growth only, we have demonstrated that uteroplacental insufficiency impairs mammary development and the lactational environment and thus reduces postnatal nutrition and growth of the offspring.19.O'Dowd R. Kent J.C. Moseley J.M. et al.The effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.Am J Physiol. 2008; 294: R539-R548Crossref PubMed Scopus (76) Google Scholar Experimentally induced uteroplacental insufficiency also reduces the number of pups at birth.14.Wlodek M.E. Mibus A.L. Tan A. et al.Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.J Am Soc Nephrol. 2007; 18: 1688-1696Crossref PubMed Scopus (166) Google Scholar,18.Wlodek M.E. Westcott K.T. O'Dowd R. et al.Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP.Am J Physiol. 2005; 288: R1620-R1627Crossref PubMed Scopus (80) Google Scholar To control for this reduction in litter size on postnatal growth, we have incorporated a second control group in our studies in which the number of pups from a control litter is reduced on day 1 to match the number of offspring in the growth-restricted (Restricted) group. We previously demonstrated that this results in postnatal growth restriction in pups born of normal weight.19.O'Dowd R. Kent J.C. Moseley J.M. et al.The effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.Am J Physiol. 2008; 294: R539-R548Crossref PubMed Scopus (76) Google Scholar In some studies, a 60–70% reduction in litter size soon after birth increases milk delivery to individual offspring, resulting in increased early postnatal growth and the development of adult obesity.20.Plagemann A. Harder T. Rake A. et al.Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats.J Neuroendocrinol. 1999; 11: 541-546Crossref PubMed Scopus (173) Google Scholar,21.Velkoska E. Cole T.J. Morris M.J. Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers.Am J Physiol. 2005; 288: E1236-E1243Crossref PubMed Scopus (112) Google Scholar,22.Faust I.M. Johnson P.R. Hirsch J. Long-term effects of early nutritional experience on the development of obesity in the rat.J Nutr. 1980; 110: 2027-2034PubMed Google Scholar In comparison, we have previously used a more modest reduction in the number of pups (from approximately 10 to 5) to match that resulting from uterine artery ligation and have found that this leads to impaired nutrition postnatally.20.Plagemann A. Harder T. Rake A. et al.Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats.J Neuroendocrinol. 1999; 11: 541-546Crossref PubMed Scopus (173) Google Scholar,21.Velkoska E. Cole T.J. Morris M.J. Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers.Am J Physiol. 2005; 288: E1236-E1243Crossref PubMed Scopus (112) Google Scholar,22.Faust I.M. Johnson P.R. Hirsch J. Long-term effects of early nutritional experience on the development of obesity in the rat.J Nutr. 1980; 110: 2027-2034PubMed Google Scholar This may be due to the reduced number of pups decreasing the suckling stimulus to the dam, which in turn decreases milk production and pup growth.19.O'Dowd R. Kent J.C. Moseley J.M. et al.The effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.Am J Physiol. 2008; 294: R539-R548Crossref PubMed Scopus (76) Google Scholar,23.Wlodek M.E. Lorenc U. O'Dowd R. et al.Uteroplacental insufficiency impairs mammary function, milk intake and postnatal growth.Pediatr Res. 2003; 53: 36AGoogle Scholar Thus, we have used this litter size reduction to induce postnatal growth restriction alone. To date, there has been little investigation into the effect of early postnatal growth restriction as an independent factor contributing to adult disease development, including hypertension. One study in which additional pups were cross-fostered onto a dam at birth to increase litter size and thereby to decrease nutritional supply received by individual pups showed that offspring slow their growth after birth. Only males were examined in that study, and it was found that offspring had a reduced number of enlarged glomeruli in their kidneys.24.Schreuder M.F. Nyengaard J.R. Remmers F. et al.Postnatal food restriction in the rat as a model for a low nephron endowment.Am J Physiol. 2006; 291: F1104-F1107Crossref PubMed Scopus (59) Google Scholar However, the limitation of that study was that blood pressure was not measured. Therefore, the first aim of this study was to compare the effects of perinatal growth restriction (where offspring are exposed to restraint before and after birth) with postnatal growth restriction (due to reduced litter size) alone on blood pressure in male offspring. Furthermore, as nephrogenesis continues after birth in the rat and thus may be influenced by postnatal nutrition and growth, we also aimed to determine the effects of perinatal and postnatal growth on nephron endowment in offspring. Similar to other studies,14.Wlodek M.E. Mibus A.L. Tan A. et al.Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.J Am Soc Nephrol. 2007; 18: 1688-1696Crossref PubMed Scopus (166) Google Scholar,25.Woods L.L. Ingelfinger J.R. Rasch R. Modest maternal protein restriction fails to program adult hypertension in female rats.Am J Physiol. 2005; 289: R1131-R1136Crossref PubMed Scopus (174) Google Scholar we chose to study male offspring to address these issues, as it is reported that males tend to be more susceptible to the development of hypertension25.Woods L.L. Ingelfinger J.R. Rasch R. Modest maternal protein restriction fails to program adult hypertension in female rats.Am J Physiol. 2005; 289: R1131-R1136Crossref PubMed Scopus (174) Google Scholar and that the mechanisms controlling blood pressure may be sex specific.26.McMullen S. Langley-Evans S.C. Maternal low-protein diet in rat pregnancy programs blood pressure through sex-specific mechanisms.Am J Physiol. 2005; 288: R85-R90Crossref PubMed Scopus (143) Google Scholar To further elucidate the mechanisms behind the effect of growth restriction on blood pressure, we examined components of the renin–angiotensin system, which play a critical role in renal development and the maintenance of blood pressure and fluid homeostasis. We and others have shown that alterations in the renal and cardiac renin–angiotensin system occur following growth restriction and that these changes correlate with increased blood pressure and altered renal development in offspring.14.Wlodek M.E. Mibus A.L. Tan A. et al.Normal lactational environment restores nephron endowment and prevents hypertension after placental restriction in the rat.J Am Soc Nephrol. 2007; 18: 1688-1696Crossref PubMed Scopus (166) Google Scholar,27.Woods L.L. Ingelfinger J.R. Nyengaard J.R. et al.Maternal protein restriction suppresses the newborn renin–angiotensin system and programs adult hypertension in rats.Pediatr Res. 2001; 49: 460-467Crossref PubMed Scopus (471) Google Scholar,28.Gilbert J.S. Lang A.L. Nijland M.J. Maternal nutrient restriction and the fetal left ventricle: decreased angiotensin receptor expression.Reprod Biol Endocrinol. 2005; 3: 27Crossref PubMed Scopus (21) Google Scholar,29.Vehaskari V.M. Stewart T. Lafont D. et al.Kidney angiotensin and angiotensin receptor expression in prenatally programmed hypertension.Am J Physiol. 2004; 287: F262-F267Crossref PubMed Scopus (127) Google Scholar Specifically, the expression of the angiotensin II type 1 (AT1) and 2 (AT2) receptors was examined in renal and cardiac tissue at 6 months of age. Gene expression studies were also performed in the adult to examine markers of tissue remodeling (including collagen, metalloproteinases (MMPs), and the tissue inhibitors of metalloproteinases (TIMPs)), as we expected fibrosis-related disease to be developing in these offspring. We hypothesized that offspring from both restricted and reduced litter groups would have a nephron deficit with altered renal and cardiac gene expression associated with increased blood pressure. Litter size on day 1 along with the body weights of male offspring at days 3, 6, and 35, at week 10, and at postmortem (6 months) are shown in Table 1. On days 3 and 6 after birth, reduced litter male pups weighed less than controls, whereas restricted pups were lighter than both control and reduced litter pups (P<0.05). Restricted male rats underwent a degree of accelerated growth between days 6 and 35, reaching weights comparable to those of the reduced litter group at day 35. However, both reduced litter and restricted groups were still lighter than control pups (P<0.05). The reduced litter male offspring underwent a period of accelerated growth after weaning so that by 10 weeks of age, their weights were comparable to control animals. Reduced litter offspring were of similar weight to controls at 6 months, whereas restricted offspring remained lighter (P<0.05).Table 1Litter size on day 1 and body weight at days 3, 6, and 35, at 10 weeks, and at 6 monthsBody weight (g)Litter sizeDay 3Day 6Day 35Week 106 monthsControl10.3±1.3b6.01±0.2c8.99±0.2c97.0±2.1b222.9±6.4366.6±7.11bRestricted4.2±0.4a4.42±0.2a6.39±0.3a74.9±3.3a206.5±6.7329.0±8.5aReduced litter4.8±0.6a5.29±0.2b7.99±0.3b73.4±6.3a225.0±6.4352.4±5.0bRestricted offspring were born small and reduced litter offspring were small by day 3 compared to control (P<0.05). Restricted offspring showed variable accelerated growth (P<0.05). Data are expressed as mean±s.e.m. (n=9–10). Significant differences (P<0.05) across the groups are indicated by different letters; for example, ‘a’ is different from ‘b.’ Open table in a new tab Restricted offspring were born small and reduced litter offspring were small by day 3 compared to control (P<0.05). Restricted offspring showed variable accelerated growth (P<0.05). Data are expressed as mean±s.e.m. (n=9–10). Significant differences (P<0.05) across the groups are indicated by different letters; for example, ‘a’ is different from ‘b.’ Perinatal or postnatal growth restriction did not alter systolic blood pressure at 5 weeks of age, although animals in the reduced litter group tended to have higher blood pressure (by ~5–8 mm Hg) compared to the control or restricted group (Figure 1a). At 9 weeks of age, the reduced litter offspring had increased blood pressure (by 14 mm Hg) compared to both control and restricted male offspring (P<0.05; Figure 1b). At 22 weeks, the restricted and reduced litter groups both had increased blood pressure (by 9 and 7 mm Hg, respectively) compared to controls (P<0.05; Figure 1c). Absolute kidney weight in male offspring of the restricted and reduced litter groups was reduced (P<0.05; Figure 2a), but not when corrected for body weight (Figure 2b). Kidney volume (measured in five animals per group) was not significantly different between the groups but tended to be lower in the restricted and reduced litter animals (control, 0.88±0.09 cm3; restricted, 0.74±0.07 cm3; and reduced litter, 0.79±0.07 cm3). A reduced glomerular number (by 36 and 27%, respectively) was found in the reduced litter and restricted groups compared to controls (P<0.05; Figure 3a). In restricted offspring, mean individual glomerular volume was increased by 27% compared to controls (P<0.05; Figure 3b), whereas there also tended to be an increase in the reduced litter group (by 20%, Figure 3b). Total glomerular volume was similar across all groups (Figure 3c).Figure 3Glomerular number and volume in male offspring. (a) Estimated total glomerular number (nephron number), (b) individual glomerular volume, and (c) total glomerular volume in male offspring at 6 months of age. Open bars represent control offspring, hatched bars offspring of the restricted group, and solid bars offspring of the reduced litter group. Growth-restricted male offspring had a nephron deficit and restricted pups had glomerular hypertrophy. Data are expressed as mean±s.e.m. (n=9–10). Significant differences (P<0.05) across the groups are indicated by different letters; for example, ‘a’ is different from ‘b’ but not different from ‘ab.’View Large Image Figure ViewerDownload (PPT) Total heart weight (as a percentage of body weight) was similar in all groups at 6 months (Figure 4a). In the restricted and reduced litter groups, left ventricle weight as a percentage of total heart weight was increased compared to controls (P<0.05; Figure 4b). The effects of perinatal and postnatal restriction on relative gene expression levels in the kidneys are shown in Table 2. There were no differences between the groups in those genes examined. Gene expression in the left ventricle was examined owing to signs of increased left ventricular mass and hypertension at 22 weeks of age in the growth-restricted groups. A significant increase in expression of the AT1A receptor was found in the left ventricle of the restricted group when compared to the control and reduced litter groups (P<0.05; Figure 5a). Expression of the AT1B receptor also tended to be increased in the restricted group, although no significant differences were detected. Expression of AT2 mRNA in the kidney and heart was not detectable after 40 cycles of PCR in any of the samples examined. There was increased expression of collagen 3 in the left ventricle of the restricted group (P<0.05; Figure 6f), and increased expression of TIMP1 (Figure 6a) in the left ventricle of the restricted group compared to the reduced litter group (P<0.05) with the control group intermediate. Relative atrial natriuretic peptide (ANP) and transforming growth factor-β1 (TGF-β1) gene expression levels in the heart were not different between the groups. Relative ANP mRNA levels in the three groups were as follows: control, 1.0±0.1; restricted, 1.1±0.3; and reduced litter, 0.7±0.1; and for TGF-β1 the relative mRNA levels were as follows: control, 1.0±0.1; restricted, 1.2±0.3; and reduced litter, 0.8±0.1.Table 2Relative renal AT1A, AT1B, TIMP1, TIMP2, MMP2, MMP9, Coll1, Coll3, and TGF-β1 receptor expression for male offspring at 6 monthsControlRestrictedReduced litterAT1A1.027±0.0921.197±0.1331.447±0.126AT1B1.056±0.1320.904±0.1341.148±0.207TIMP11.104±0.1841.230±0.1991.301±0.235TIMP21.110±0.1970.853±0.1101.005±0.119MMP21.279±0.2991.563±0.2891.871±0.217MMP91.135±0.1932.285±0.7992.752±0.966Coll11.322±0.3331.442±0.2701.725±0.162Coll31.186±0.2521.042±0.1231.495±0.153TGF-β11.190±0.2300.948±0.1550.740±0.157AT, angiotensin II type; Coll, collagen; MMP, metalloproteinase; TGF-β1, transforming growth factor-β1; TIMP, tissue inhibitor of metalloproteinase.Values are expressed relative to a calibrator (the control group). There were no differences in renal gene expression across the groups. Data are expressed as mean±s.e.m. (n=9–10). Open table in a new tab Figure 6Gene expression in the left ventricle. Relative gene expression of (a) TIMP1, (b) TIMP2, (c) MMP2, (d) MMP9, (e), collagen 1 (Coll1), and (f) collagen 3 (Coll3) in the left ventricle of male offspring at 6 months of age. Open bars represent control offspring, hatched bars offspring of the restricted group, and solid bars offspring of the reduced litter group. Both growth-restricted groups had increased expression of TIMP1 and Coll3 (P<0.05). Data are expressed as mean±s.e.m. (n=9–10). Significant differences (P<0.05) across the groups are indicated by different letters; for example, ‘a’ is different from ‘b.’View Large Image Figure ViewerDownload (PPT) AT, angiotensin II type; Coll, collagen; MMP, metalloproteinase; TGF-β1, transforming growth factor-β1; TIMP, tissue inhibitor of metalloproteinase. Values are expressed relative to a calibrator (the control group). There were no differences in renal gene expression across the groups. Data are expressed as mean±s.e.m. (n=9–10). This study demonstrates that reduction of litter size at birth, with the associated compromised nutrition and growth in the early postnatal period, not only induces a nephron deficit in adult male offspring but also results in elevated blood pressure. This occurs even though offspring are born with a normal birth weight. The nephron deficit induced by the reduction in litter size and postnatal growth restriction was similar in magnitude to that observed in animals that experienced growth restriction before and after birth due to uteroplacental insufficiency, suggesting that renal development in the rat can be profoundly affected by postnatal events. Growth restriction in the postnatal period also increased left ventricular mass, indicating that hypertension may be contributing to other aspects of disease development. In this study, we induced postnatal growth restriction by reducing litter size at birth from approximately 10 down to 5 pups. A reduction of litter size at birth has been used in many studies to act as a ‘control’ group for various models (for example, maternal nutritional interventions and placental insufficiency); however, the effects on growth of the remaining offspring tend to be variable. Others have reported that a severe reduction in pup number (by approximately 70%) has been shown to result in accelerated postnatal growth, presumably due to increased nutrition to individual pups.20.Plagemann A. Harder T. Rake A. et al.Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats.J Neuroendocrinol. 1999; 11: 541-546Crossref PubMed Scopus (173) Google Scholar,21.Velkoska E. Cole T.J. Morris M.J. Early dietary intervention: long-term effects on blood pressure, brain neuropeptide Y, and adiposity markers.Am J Physiol. 2005; 288: E1236-E1243Crossref PubMed Scopus (112) Google Scholar,22.Faust I.M. Johnson P.R. Hirsch J. Long-term effects of early nutritional experience on the development of obesity in the rat.J Nutr. 1980; 110: 2027-2034PubMed Google Scholar,30.Auldist D.E. Carlson D. Morrish L. et al.The influence of suckling interval on milk production of sows.J Anim Sci. 2000; 78: 2026-2031PubMed Google Scholar,31.Babicky A. Ostadalova I. Parizek J. et al.Onset and duration of the physiological weaning period for infant rats reared in nests of different sizes.Physiol Bohemoslov. 1972; 22: 449-456Google Scholar However, we have recently reported in our model that litter reduction removes the stimulus for increased milk production, which normally occurs after birth, resulting in lower maternal milk production and altered composition, thus slowing postnatal growth.19.O'Dowd R. Kent J.C. Moseley J.M. et al.The effects of uteroplacental insufficiency and reducing litter size on maternal mammary function and postnatal offspring growth.Am J Physiol. 2008; 294: R539-R548Crossref PubMed Scopus (76) Google Scholar However, the postnatal growth restriction may only be partially responsible for the outcomes observed in this study, as we cannot discount that removal of pups may stimulate a stress response in the dam subjected to a reduction in the number of suckling pups, which may potentially inhibit lactation32.Tu M.T. Lupien S.J. Walker C.D. Measuring stress responses in postpartum mothers: perspectives from studies in human and animal populations.Stress. 2005; 8: 19-34Crossref PubMed Scopus (61) Google Scholar,33.Champagne F.A. Meaney M.J. Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model.Biol Psychiatry. 2006; 59: 1227-1235Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar,34.Deschamps S. Woodside B. Walker C.D. Pups' presence eliminates the stress hyporesponsiveness of early lactating females to a psychological stress representing a threat to the pups.J Neuroendocrinol. 2003; 15: 486-497Crossref PubMed Sc" @default.
• W1972339030 created "2016-06-24" @default.
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• W1972339030 date "2008-07-01" @default.
• W1972339030 modified "2023-10-09" @default.
• W1972339030 title "Growth restriction before or after birth reduces nephron number and increases blood pressure in male rats" @default.
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