Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats

Gallo, Linda A.; Tran, Melanie; Cullen‐McEwen, Luise A.; Denton, Kate M.; Jefferies, Andrew J.; Wlodek, Mary E.

doi:10.1071/rd13133

Cited by 35 publications

(56 citation statements)

References 49 publications

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“…Although F1 growth-restricted male offspring have increased blood pressure as previously published (7,12,18), our model of growth restriction does not program obesity (17,44). Previous studies have demonstrated that F0 paternal obesity adversely affects embryo development and function, which can lead to the development of F1 cardiovascular and metabolic dysfunction (19,20,24).…”

Section: Discussionmentioning

confidence: 50%

“…Although both F1 male and female offspring have organ deficits, only F1 male rats develop hypertension and metabolic dysfunction in the absence of obesity (7,(9)(10)(11)(12). We, and others, have also demonstrated that these deficits are not limited to F1 offspring and can be transmitted, by mothers born small, to the second generation (13)(14)(15)(16)(17)(18). The second-generation (F2) transgenerational effects transmitted via the F1 paternal line after growth restriction are less well characterized.…”

Section: Introductionmentioning

confidence: 88%

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Fathers That Are Born Small Program Alterations in the Next-Generation Preimplantation Rat Embryos ,

Master

Thouas

Harvey

et al. 2015

The Journal of Nutrition

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The findings from this study clearly indicate that male rat offspring born small, arising from uteroplacental insufficiency, have physiologic alterations that manifest as modifications in gene expression levels and nutrient metabolism of F2 blastocysts, even in the absence of overt cellular growth differences. These data demonstrate that growth restriction and associated disease risk have the capacity to be transmitted to the next generation of offspring via the male germ line and is manifest as early as the blastocyst stage of development.

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 88%

Fathers That Are Born Small Program Alterations in the Next-Generation Preimplantation Rat Embryos ,

Master

Thouas

Harvey

et al. 2015

The Journal of Nutrition

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“…2009; Gallo et al. 2012a, 2013). Urinary measurements of sodium, chloride, potassium (Rapidchem 744, Bayer Healthcare, CA), glucose, creatinine, albumin, and total protein (Cobas Integra 400; Roche Diagnostics, Burgess Hill, UK) were performed.…”

Section: Methodsmentioning

confidence: 99%

Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats

et al. 2015

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Growth restriction impacts on offspring development and increases their risk of disease in adulthood which is exacerbated with “second hits.” The aim of this study was to investigate if blood pressure, glucose tolerance, and skeletal muscle mitochondrial biogenesis were altered in 12-month-old male and female offspring with prenatal or postnatal growth restriction. Bilateral uterine vessel ligation induced uteroplacental insufficiency and growth restriction in offspring (Restricted). A sham surgery was also performed during pregnancy (Control) and some litters from sham mothers had their litter size reduced (Reduced litter), which restricted postnatal growth. Growth-restricted females only developed hypertension at 12 months, which was not observed in males. In Restricted females only homeostasis model assessment for insulin resistance was decreased, indicating enhanced hepatic insulin sensitivity, which was not observed in males. Plasma leptin was increased only in the Reduced males at 12 months compared to Control and Restricted males, which was not observed in females. Compared to Controls, leptin, ghrelin, and adiponectin were unaltered in the Restricted males and females, suggesting that at 12 months of age the reduction in body weight in the Restricted offspring is not a consequence of circulating adipokines. Skeletal muscle PGC-1α levels were unaltered in 12-month-old male and female rats, which indicate improvements in lean muscle mass by 12 months of age. In summary, sex strongly impacts the cardiometabolic effects of growth restriction in 12-month-old rats and it is females who are at particular risk of developing long-term hypertension following growth restriction.

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“…Female offspring which were not hypertensive had normal mesenteric, renal, and femoral artery stiffness but had uterine artery endothelial dysfunction and increased wall stiffness [109••]. Utero-placental insufficiency has been shown to decrease nephron number and cyclooxygenase-2 (COX-2) in a rat model [110] and to increase umbilical and carotid artery stiffness in sheep dams due to disrupted extracellular matrix deposition [111]. Increased markers of renal apoptosis and decreased urinary sodium excretion [112] were also noted in rats and newborn piglets.…”

Section: Pathogenesis Of Primary Pediatric Hypertensionmentioning

confidence: 99%

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

et al. 2017

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The rising prevalence of primary pediatric hypertension and its tracking into adult hypertension point to the importance of determining its pathogenesis to gain insights into its current and emerging management. Considering that the intricate control of BP is governed by a myriad of anatomical, molecular biological, biochemical, and physiological systems, multiple genes are likely to influence an individual's BP and susceptibility to develop hypertension. The long-term regulation of BP rests on renal and non-renal mechanisms. One renal mechanism relates to sodium transport. The impaired renal sodium handling in primary hypertension and salt sensitivity may be caused by aberrant counter-regulatory natriuretic and anti-natriuretic pathways. The sympathetic nervous and renin-angiotensin-aldosterone systems are examples of antinatriuretic pathways. An important counter-regulatory natriuretic pathway is afforded by the renal autocrine/paracrine dopamine system, aberrations of which are involved in the pathogenesis of hypertension, including that associated with obesity. We present updates on the complex interactions of these two systems with dietary salt intake in relation to obesity, insulin resistance, inflammation, and oxidative stress. We review how insults during pregnancy such as maternal and paternal malnutrition, glucocorticoid exposure, infection, placental insufficiency, and treatments during the neonatal period have long-lasting effects in the regulation of renal function and BP. Moreover, these effects have sex differences. There is a need for early diagnosis, frequent monitoring, and timely management due to increasing evidence of premature target organ damage. Large controlled studies are needed to evaluate the long-term consequences of the treatment of elevated BP during childhood, especially to establish the validity of the current definition and treatment of pediatric hypertension.

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Transgenerational programming of fetal nephron deficits and sex-specific adult hypertension in rats

Cited by 35 publications

References 49 publications

Fathers That Are Born Small Program Alterations in the Next-Generation Preimplantation Rat Embryos ,

Fathers That Are Born Small Program Alterations in the Next-Generation Preimplantation Rat Embryos ,

Uteroplacental insufficiency leads to hypertension, but not glucose intolerance or impaired skeletal muscle mitochondrial biogenesis, in 12-month-old rats

Primary Pediatric Hypertension: Current Understanding and Emerging Concepts

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