Maternal low-protein diet during mouse pre-implantation development induces vascular dysfunction and altered renin-angiotensin-system homeostasis in the offspring

School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, UK.
The British journal of nutrition (Impact Factor: 3.45). 06/2010; 103(12):1762-70. DOI: 10.1017/S0007114509993783
Source: PubMed


Environmental perturbations during early mammalian development can affect aspects of offspring growth and cardiovascular health. We have demonstrated previously that maternal gestational dietary protein restriction in mice significantly elevated adult offspring systolic blood pressure. Therefore, the present study investigates the key mechanisms of blood pressure regulation in these mice. Following mating, female MF-1 mice were assigned to either a normal-protein diet (NPD; 18 % casein) or an isocaloric low-protein diet throughout gestation (LPD; 9 % casein), or fed the LPD exclusively during the pre-implantation period (3.5 d) before returning to the NPD for the remainder of gestation (Emb-LPD). All offspring received standard chow. At 22 weeks, isolated mesenteric arteries from LPD and Emb-LPD males displayed significantly attenuated vasodilatation to isoprenaline (P = 0.04 and P = 0.025, respectively), when compared with NPD arteries. At 28 weeks, stereological analysis of glomerular number in female left kidneys revealed no significant difference between the groups. Real-time RT-PCR analysis of type 1a angiotensin II receptor, Na+/K+ ATPase transporter subunits and glucocorticoid receptor expression in male and female left kidneys revealed no significant differences between the groups. LPD females displayed elevated serum angiotensin-converting enzyme (ACE) activity (P = 0.044), whilst Emb-LPD males had elevated lung ACE activity (P = 0.001), when compared with NPD offspring. These data demonstrate that elevated offspring systolic blood pressure following maternal gestational protein undernutrition is associated with impaired arterial vasodilatation in male offspring, elevated serum and lung ACE activity in female and male offspring, respectively, but kidney glomerular number in females and kidney gene expression in male and female offspring appear unaffected.


Available from: Emma S Lucas, Feb 13, 2014
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    • "A maternal low protein diet fed during the preimplantation period of rat development caused blastocyst abnormalities and altered birth weight, postnatal growth rate, and adult hypertension [7], [8]. Similarly, a low protein diet administered exclusively during the preimplantation period in mice resulted in increased weight after birth, cardiovascular pathologies, perturbations to renin-angiotensin homeostasis, and abnormal anxiety-related behavior in the offspring [9], [10]. Furthermore, a maternal high fat diet prior to conception is associated with mouse oocytes and zygotes that have altered mitochondrial function including increased membrane potential and biogenesis and increased reactive oxygen species [11]. "
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    ABSTRACT: Maternal nutrition exclusively during the periconceptional period can induce remarkable effects on both oocyte maturation and early embryo development, which in turn can have lifelong consequences. The objective of this study was to evaluate the effect of maternal methionine supplementation on the transcriptome of bovine preimplantation embryos. Holstein cows were randomly assigned to one of two treatments differing in level of dietary methionine (1.89 Met vs. 2.43 Met % of metabolizable protein) from calving until embryo flushing. High quality preimplantation embryos from individual cows were pooled and then analyzed by RNA sequencing. Remarkably, a subtle difference in methionine supplementation in maternal diet was sufficient to cause significant changes in the transcriptome of the embryos. A total of 276 genes out of 10,662 showed differential expression between treatments (FDR <0.10). Interestingly, several of the most significant genes are related to embryonic development (e.g., VIM, IFI6, BCL2A1, and TBX15) and immune response (e.g., NKG7, TYROBP, SLAMF7, LCP1, and BLA-DQB). Likewise, gene set enrichment analysis revealed that several Gene Ontology terms, InterPro entries, and KEGG pathways were enriched (FDR <0.05) with differentially expressed genes involved in embryo development and immune system. The expression of most genes was decreased by maternal methionine supplementation, consistent with reduced transcription of genes with increased methylation of specific genes by increased methionine. Overall, our findings provide evidence that supplementing methionine to dams prior to conception and during the preimplantation period can modulate gene expression in bovine blastocysts. The ramifications of the observed gene expression changes for subsequent development of the pregnancy and physiology of the offspring warrant further investigation in future studies.
    PLoS ONE 08/2013; 8(8):e72302. DOI:10.1371/journal.pone.0072302 · 3.23 Impact Factor
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    • "The RAS plays an important role in fetal growth restriction and the development of hypertension in response to maternal low-protein diet. Decreased nephron endowment and glomerular hypertrophy are accompanied by suppression of the newborn intrarenal RAS, system essential for normal kidney development [99–102]. In addition, maternal low-protein diet increases the risk of salt-sensitive hypertension [57]. "
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    ABSTRACT: A growing body of evidence supports the concept that changes in the intrauterine milieu during "sensitive" periods of embryonic development or in infant diet after birth affect the developing individual, resulting in general health alterations later in life. This phenomenon is referred to as "developmental programming" or "developmental origins of health and disease." The risk of developing late-onset diseases such as hypertension, chronic kidney disease (CKD), obesity or type 2 diabetes is increased in infants born prematurely at <37 weeks of gestation or in low birth weight (LBW) infants weighing <2,500 g at birth. Both genetic and environmental events contribute to the programming of subsequent risks of CKD and hypertension in premature or LBW individuals. A number of observations suggest that susceptibility to subsequent CKD and hypertension in premature or LBW infants is mediated, at least in part, by reduced nephron endowment. The major factors influencing in utero environment that are associated with a low final nephron number include uteroplacental insufficiency, maternal low-protein diet, hyperglycemia, vitamin A deficiency, exposure to or interruption of endogenous glucocorticoids, and ethanol exposure. This paper discusses the effect of premature birth, LBW, intrauterine milieu, and infant feeding on the development of hypertension and renal disease in later life as well as examines the role of the kidney in developmental programming of hypertension and CKD.
    International Journal of Nephrology 11/2012; 2012(4):760580. DOI:10.1155/2012/760580
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    • "Epidemiological and animal studies show that cardiovascular dysfunction, kidney disease, and alterations in the renin–angiotensin system might be related to the undernutrition state in critical stages of development and childhood (Benabe et al. 1993; Whorwood et al. 2001; Sesso et al. 2004; Barker 2007; Harrison and Langley- Evans 2009). Most of the effects of protein deficits on cardiac function have been evaluated during pregnancy, focusing on offspring development or the consequences of dramatic changes in the nutrition profile (Langley-Evans et al. 1994; Lucas 1995; Cheema et al. 2005; Prentice et al. 2005; Elmes et al. 2008; Watkins et al. 2010). For example, Cheema et al. (2005) showed that a low-protein (LP) diet during pregnancy induces cardiovascular dysfunction throughout the life of the offspring , indicated by decreased cardiac output and the maximum rates of contraction and relaxation, in addition to increased left ventricular end-diastolic pressure and cardiomyocyte apoptosis (Cheema et al. 2005). "
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    ABSTRACT: Undernutrition during critical stages of development and childhood has important effects on cardiovascular homeostasis. The present study was undertaken to evaluate the in vivo and ex vivo cardiac function of rats submitted to postnatal protein restriction. Male Wistar rats (28 days old) were fed a regular (20%) or low-protein (6%) diet over 5 weeks. After this period, cardiac function was analyzed by echocardiography and isolated heart preparation. Furthermore, the density of cardiac noradrenergic fibers and hematological profile were evaluated. We found that malnourished rats exhibited elevated arterial blood pressure, increased fractional shortening (echocardiography), increased systolic tension, increased ±dT/dt (isolated heart technique), impaired diastolic function characterized by a slight increase in the left ventricular end-diastolic diameter (echocardiography) and decreased diastolic tension (isolated heart technique), and cardiac hypertrophy evidenced by augmentation of the posterior left ventricular wall and discrete hematological changes. In addition, malnourished rats exhibited increased noradrenergic fiber density in their hearts (0.08% ± 0.02% area in control rats vs. 0.17% ± 0.03% area in malnourished rats). Our current data demonstrate that postnatal protein restriction causes cardiac adaptation characterized by an early overworking heart. This is at least in part mediated by an increase in the efferent sympathetic fibers to the heart. These findings provide important information for efforts to prevent and manage the consequences of undernutrition in the human population.
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