Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control

2011 ◽  
Vol 301 (2) ◽  
pp. R500-R509 ◽  
Author(s):  
Karen M. Moritz ◽  
Robert De Matteo ◽  
Miodrag Dodic ◽  
Andrew J. Jefferies ◽  
Debbie Arena ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Function ◽  
Arterial Pressure ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Salt Intake ◽  
Female Offspring ◽  
In Utero ◽  
Late Gestation ◽  
Elevated Arterial Pressure

Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX; 0.48 mg/h) or cortisol (CORT; 5 mg/h) over days 26–28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (α-, β-, γ-subunits) and Na+-K+-ATPase (α-, β-, γ-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period.

Endocrine regulation of fetal growth

1995 ◽  
Vol 7 (3) ◽  
pp. 351 ◽  
Author(s):  
AL Fowden
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Fetal Growth ◽  
Growth Regulation ◽  
Fetal Liver ◽  
In Utero ◽  
Tissue Differentiation ◽  
Late Gestation ◽  
Endocrine Regulation ◽  
Tissue Accretion

Hormones have an important role in the control of fetal growth. They act on both tissue accretion and differentiation and enable a precise and orderly pattern of growth to occur during late gestation. In part, their actions on growth may be mediated by other growth factors such as the insulin-like growth factors (IGFs). Insulin stimulates fetal growth by increasing the mitotic drive and nutrient availability for tissue accretion. It has little effect on tissue differentiation. In contrast, the main effects of cortisol in utero are on tissue differentiation and maturation. Cortisol appears to act directly on the cells to alter gene transcription or post-translational processing of the gene products. Cortisol may also initiate the transition from the fetal to the adult modes of growth regulation by inducing the switch from IGF-II to IGF-I gene expression in the fetal liver. Thyroxine affects both tissue accretion and differentiation in the fetus by a combination of metabolic and non-metabolic mechanisms. Pituitary growth hormone, on the other hand, appears to have little part in the control of fetal growth, unlike its role postnatally. Fetal hormones, therefore, promote growth and development in utero by altering both the metabolism and gene expression of the fetal tissues. These hormonal actions ensure that fetal growth rate is commensurate with the nutrient supply and that prepartum maturation occurs in preparation for extrauterine life.

Interactions between subtotal nephrectomy and salt: effects on blood pressure and renal function in pregnant and nonpregnant ewes

2008 ◽  
Vol 294 (4) ◽  
pp. R1227-R1233 ◽  
Author(s):  
Karen J. Gibson ◽  
Amanda C. Boyce ◽  
Clare L. Thomson ◽  
Sarah Chinchen ◽  
Eugenie R. Lumbers
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Salt Intake ◽  
High Salt ◽  
Late Gestation ◽  
Plasma Creatinine ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
High Salt Intake ◽  
In Pregnancy

The effects of high salt intake on blood pressure and renal function were studied in nine subtotally nephrectomized pregnant ewes (STNxP) and seven intact pregnant ewes (IntP) in late gestation and in eight subtotally nephrectomized nonpregnant ewes (STNxNP) and seven intact nonpregnant ewes (IntNP). STNxP had higher mean arterial pressures ( P < 0.02) and plasma creatinine levels ( P < 0.001) than IntP. High salt (0.17 M NaCl as drinking water for 5 days) did not change blood pressure in either STNxP or IntP. STNxNP had higher mean arterial pressures ( P = 0.03) and plasma creatinine levels ( P < 0.001) than IntNP. In STNxNP, blood pressure increased with high salt intake and there was a positive relationship between diastolic pressure and sodium balance ( r = 0.497, P = 0.05). This relationship was not present in IntNP, STNxP, or IntP. Because high salt intake did not cause an increase in blood pressure in STNxP, it is concluded that they were protected by pregnancy from further rises in blood pressure. The observed increase in glomerular filtration rate ( P < 0.03) and depression of fractional proximal sodium reabsorption ( P = 0.003) that occurred in STNxP, but not in STNxNP, in response to high salt may have contributed to this protection. As well, the increased production of vasorelaxants in pregnancy may selectively protect against the occurrence of salt-sensitive hypertension in pregnancy.

scholarly journals Untargeted metabolomics reveals sex-specific differences in lipid metabolism of adult rats exposed to dexamethasone in utero

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alyssa Murray ◽  
Sujeenthar Tharmalingam ◽  
Phong Nguyen ◽  
T. C. Tai
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Hepatic Metabolism ◽  
Female Offspring ◽  
In Utero ◽  
Glutathione Metabolism ◽  
Lipid Profiling ◽  
Adult Rats ◽  
Increased Risk ◽  
Wistar Kyoto

AbstractPrenatal stress through glucocorticoid (GC) exposure leads to an increased risk of developing diseases such as cardiovascular disease, metabolic syndrome and hypertension in adulthood. We have previously shown that administration of the synthetic glucocorticoid, dexamethasone (Dex), to pregnant Wistar–Kyoto dams produces offspring with elevated blood pressures and disrupted circadian rhythm signaling. Given the link between stress, circadian rhythms and metabolism, we performed an untargeted metabolomic screen on the livers of offspring to assess potential changes induced by prenatal Dex exposure. This metabolomic analysis highlighted 18 significantly dysregulated metabolites in females and 12 in males. Pathway analysis using MetaboAnalyst 4.0 highlighted key pathway-level metabolic differences: glycerophospholipid metabolism, purine metabolism and glutathione metabolism. Gene expression analysis revealed significant upregulation of several lipid metabolism genes in females while males showed no dysregulation. Triglyceride concentrations were also found to be significantly elevated in female offspring exposed to Dex in utero, which may contribute to lipid metabolism activation. This study is the first to conduct an untargeted metabolic profile of liver from GC exposed offspring. Corroborating metabolic, gene expression and lipid profiling results demonstrates significant sex-specific lipid metabolic differences underlying the programming of hepatic metabolism.

scholarly journals Effect of Changes in Salt Intake on Arterial Pressure and Renal Function in Partially Nephrectomized Dogs

1963 ◽  
Vol 12 (5) ◽  
pp. 508-513 ◽  
Author(s):  
JIMMY B. LANGSTAN ◽  
ARTHUR C. GUYTOM ◽  
B. H. DOUGLAS ◽  
P. E. DORSETT ◽  
Ann Russel ◽  
...  
Keyword(s):  
Renal Function ◽  
Arterial Pressure ◽  
Salt Intake

Combined prenatal and postnatal protein restriction influences adult kidney structure, function, and arterial pressure

2007 ◽  
Vol 292 (1) ◽  
pp. R462-R469 ◽  
Author(s):  
Chantal C. Hoppe ◽  
Roger G. Evans ◽  
Karen M. Moritz ◽  
Luise A. Cullen-McEwen ◽  
Sharyn M. Fitzgerald ◽  
...  
Keyword(s):  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Arterial Pressure ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Salt Intake ◽  
Renal Plasma Flow ◽  
Protein Restriction ◽  
Nephron Number

The effects of prenatal protein restriction on adult renal and cardiovascular function have been studied in considerable detail. However, little is known about the effects of life-long protein restriction, a common condition in the developing world. Therefore, we determined in rats the effects of combined pre- and postnatal protein restriction on adult arterial pressure and renal function and responses to increased dietary sodium. Nephron number was also determined. Male Sprague-Dawley rats were born to mothers fed a low [8% (wt/wt), LP] or normal [20% (wt/wt), NP] isocaloric protein diet throughout pregnancy and maintained on these diets after birth. At postnatal day 135, nephron number, mean arterial pressure (MAP), and renal function were determined. A high-NaCl [8.0% (wt/wt), high-salt] diet was fed to a subset of rats from weaning. MAP was less in LP than in NP rats (120 ± 2 vs. 128 ± 2 mmHg, P < 0.05) and was not significantly altered by increased salt intake. Nephron number was 31% less in LP than in NP rats ( P < 0.001). The volume of individual glomeruli was also less in LP than in NP rats, as were calculated effective renal plasma flow and glomerular filtration rate. Glomerular filtration rate, but not effective renal plasma flow, appeared to be increased by high salt intake, particularly in LP rats. In conclusion, protein restriction induced a severe nephron deficit, but MAP was lower, rather than higher, in protein-restricted than in control rats in adulthood. These findings indicate that the postnatal environment plays a key role in determining the outcomes of developmental programming.

scholarly journals Serum aldosterone regulation, blood pressure response to high salt intake and renal function and structure in adult female offspring are modified by salt overload during pregnancy

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Edson Nogueira Alves Rodrigues ◽  
Ivone B. Oliveira ◽  
Luzia NS. Furukawa ◽  
Daniele N. Ferreira ◽  
Michella S. Coelho ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Adult Female ◽  
Salt Intake ◽  
Blood Pressure Response ◽  
Female Offspring ◽  
Pressure Response ◽  
High Salt ◽  
Serum Aldosterone ◽  
High Salt Intake

scholarly journals Toll-Like Receptor-4 Antagonist (+)-Naloxone Confers Sexually Dimorphic Protection From Inflammation-Induced Fetal Programming in Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (11) ◽  
pp. 2646-2662 ◽  
Author(s):  
Peck Yin Chin ◽  
Camilla Dorian ◽  
David J Sharkey ◽  
Mark R Hutchinson ◽  
Kenner C Rice ◽  
...  
Keyword(s):  
Fetal Brain ◽  
Later Life ◽  
Female Offspring ◽  
Developmental Programming ◽  
In Utero ◽  
Cytokine Expression ◽  
Late Gestation ◽  
Toll Like Receptor ◽  
Fetal Sex ◽  
Lps Challenge

Abstract Inflammation elicited by infection or noninfectious insults during gestation induces proinflammatory cytokines that can shift the trajectory of development to alter offspring phenotype, promote adiposity, and increase susceptibility to metabolic disease in later life. In this study, we use mice to investigate the utility of a small molecule Toll-like receptor (TLR)4 antagonist (+)-naloxone, the nonopioid isomer of the opioid receptor antagonist (−)-naloxone, for mitigating altered fetal metabolic programming induced by a modest systemic inflammatory challenge in late gestation. In adult progeny exposed to lipopolysaccharide (LPS) challenge in utero, male but not female offspring exhibited elevated adipose tissue, reduced muscle mass, and elevated plasma leptin at 20 weeks of age. Effects were largely reversed by coadministration of (+)-naloxone following LPS. When given alone without LPS, (+)-naloxone elicited accelerated postweaning growth and elevated muscle and fat mass in adult male but not female offspring. LPS induced expression of inflammatory cytokines Il1a, Il1b, Il6, Tnf, and Il10 in fetal brain, placental, and uterine tissues, and (+)-naloxone suppressed LPS-induced cytokine expression. Fetal sex-specific regulation of cytokine expression was evident, with higher Il1a, Il1b, Il6, and Il10 induced by LPS in tissues associated with male fetuses, and greater suppression by (+)-naloxone of Il6 in females. These data demonstrate that modulating TLR4 signaling with (+)-naloxone provides protection from inflammatory diversion of fetal developmental programming in utero, associated with attenuation of gestational tissue cytokine expression in a fetal sex-specific manner. The results suggest that pharmacologic interventions targeting TLR4 warrant evaluation for attenuating developmental programming effects of fetal exposure to maternal inflammatory mediators.

scholarly journals Sexual Dimorphism in Offspring Glucose-Sensitive Hypothalamic Gene Expression and Physiological Responses to Maternal High-Fat Diet Feeding

Endocrinology ◽  
2014 ◽  
Vol 155 (6) ◽  
pp. 2144-2154 ◽  
Author(s):  
Laura Dearden ◽  
Nina Balthasar
Keyword(s):  
Gene Expression ◽  
Sexual Dimorphism ◽  
Glucose Homeostasis ◽  
Maternal Diet ◽  
Female Offspring ◽  
In Utero ◽  
High Fat ◽  
Metabolic Balance ◽  
High Sugar ◽  
Female Specific

A wealth of animal and human studies demonstrate that early life environment significantly influences adult metabolic balance, however the etiology for offspring metabolic misprogramming remains incompletely understood. Here, we determine the effect of maternal diet per se on offspring sex-specific outcomes in metabolic health and hypothalamic transcriptome regulation in mice. Furthermore, to define developmental periods of maternal diet misprogramming aspects of offspring metabolic balance, we investigated offspring physiological and transcriptomic consequences of maternal high-fat/high-sugar diet feeding during pregnancy and/or lactation. We demonstrate that female offspring of high-fat/high-sugar diet-fed dams are particularly vulnerable to metabolic perturbation with body weight increases due to postnatal processes, whereas in utero effects of the diet ultimately lead to glucose homeostasis dysregulation. Furthermore, glucose- and maternal-diet sensitive gene expression modulation in the paraventricular hypothalamus is strikingly sexually dimorphic. In summary, we uncover female-specific, maternal diet-mediated in utero misprogramming of offspring glucose homeostasis and a striking sexual dimorphism in glucose- and maternal diet-sensitive paraventricular hypothalamus gene expression adjustment. Notably, female offspring metabolic vulnerability to maternal high-fat/high-sugar diet propagates a vicious cycle of obesity and type 2 diabetes in subsequent generations.

Sign in / Sign up

Export Citation Format

Share Document