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Biomedical subjects

E Marelyn Wintour

Publications and source records attributed to E Marelyn Wintour.

At least 19 recordsLinked to original sources
PubMed2006

Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse.

We investigated the effects of maternal glucocorticoid exposure in the spiny mouse, a precocial species with a relatively long gestation, few offspring, and in which nephrogenesis is complete before birth. We hypothesized that exposure of the fetus to glucocorticoids before the formation of glomeruli would result in adult hypertensive offspring with fewer nephrons. Furthermore, we hypothesized that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at midgestation (day 20) delivered dexamethasone (dex; 125 microg/kg) or saline for 60 h. Females were killed at day 23 of gestation and kidneys were frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 wk of age, blood pressure was measured in the offspring for 1 wk before nephron number was determined using unbiased stereology. Males and females exposed to dex had significantly fewer nephrons (male: saline: 7,870 +/- 27, dex: 6,878 +/- 173; female: saline: 7,526 +/- 62, dex: 5,886 +/- 382; P < 0.001) compared with controls. Dex had no effect on basal blood pressure. Fetal kidneys collected at day 23 of gestation from dex-exposed mothers showed increased mRNA expression of BMP4 (P < 0.05), TGF-beta(1) (P < 0.05), genes known to inhibit branching morphogenesis and gremlin (P < 0.01), an antagonist of BMP4, compared with saline controls. This study shows for the first time an upregulation of branching morphogenic genes in the fetal kidney in a model of excess maternal glucocorticoids that leads to a nephron deficit in the adult. This study also provides evidence that a reduced nephron number does not necessarily lead to development of hypertension.

Animals↗
PubMed2006

Glycerol transport: an additional target for obesity therapy?

There is increasing evidence that the glycerol channel, aquaporin 7(AQP7), has an important role in adipose tissue formation and function--deletion of the gene in a mouse strain leads to obesity and diabetes type 2 if the mice are aged or fed earlier with a high-fat or sucrose diet. Can increased levels of AQP7 in adipose tissue protect against obesity? New studies on AQP7 highlight the important role of glycerol transport in the development of obesity and metabolic disease.

Adipose Tissue↗
PubMed2006

Aquaporins: a promising target for drug development.

Aquaporins (AQPs) are a family of small hydrophobic, integral membrane proteins that are expressed in all living organisms and play critical roles in controlling the water flow into and out of cells. So far, 13 different AQPs have been identified in mammals (AQP 0-12). AQPs have recently been implicated in various diseases such as cancer, cataract, brain oedema, gallstone disease and nephrogenic diabetes insipidus, as well as in the development of obesity and polycystic kidney disease. Interfering with the expression of AQPs will undoubtedly have therapeutic applications. Hence, in this review, the authors look at each AQP and its association with various pathological conditions in humans and demonstrate that they form potential targets for the treatment of such diseases.

Animals↗
PubMed2005

Glucocorticoid programming of adult disease.

Fetal exposure to elevated levels of glucocorticoids can occur naturally when maternal glucocorticoids are elevated in times of stress or when exogenous glucocorticoids are administered. Epidemiological studies and animal models have shown that, whereas short-term benefits may be associated with fetal glucocorticoid exposure, long-term deleterious effects may arise. This review compares the effects of exposure to natural versus synthetic glucocorticoids and considers the ways in which the timing of the exposure and the sex of the fetus may influence outcomes. Some of the long-term effects of glucocorticoid exposure may be explained by epigenetic mechanisms.

Animals↗
PubMed2005

Effects of 7-day amino acid infusion on renal growth, function, and renin-angiotensin system in fetal sheep.

These experiments examined whether renal growth and the fetal renin-angiotensin system could be stimulated by infusion of amino acids and whether chronic amino acid infusions restored glomerulotubular balance, which had been disrupted during 4-h infusions. Five fetal sheep aged 122 +/- 1 days gestation received an infusion of alanine, glycine, proline and serine in 0.15 M saline at 0.22 mmol/min for 7 days. Six control fetuses were given saline at the same rate (5 ml/h). Kidney wet weights after amino acid infusion were 28% larger than control fetuses (P < 0.05), and renal angiotensinogen mRNA levels were approximately 2.6-fold higher (P < 0.005). Circulating renin levels and renal renin mRNA levels were suppressed (P < 0.05), and renal renin protein levels tended to be lower. Arterial pressure was increased, and there was a marked, sustained natriuresis and diuresis. Glomerular filtration rate and filtered sodium were approximately two-fold higher throughout infusion (P < 0.05). Fractional proximal sodium reabsorption, suppressed at 4 h (from 73.4 +/- 6.5 to 53.7 +/- 10.2%), did not return to control levels (36.1 +/- 3.4% on day 7, P < 0.05). Distal sodium reabsorption was markedly increased (from 79 +/- 25 to 261 +/- 75 mumol/min by day 7, P < 0.005), but this was not sufficient to restore glomerulotubular balance. The resultant high rates of sodium excretion led to hyponatremia and polyhydramnios. In conclusion, long-term amino acid infusions increased renal angiotensinogen gene expression, kidney weight, and distal nephron sodium reabsorptive capacity but failed to restore proximal and total glomerulotubular balance.

Amino Acids↗
PubMed2005

Aquaporins in development -- a review.

Water homeostasis during fetal development is of crucial physiologic importance. It depends upon maternal fetal fluid exchange at the placenta and fetal membranes, and some exchange between fetus and amniotic fluid can occur across the skin before full keratinization. Lungs only grow and develop normally with fluid secretion, and there is evidence that cerebral spinal fluid formation is important in normal brain development. The aquaporins are a growing family of molecular water channels, the ontogeny of which is starting to be explored. One question that is of particular importance is how well does the rodent (mouse, rat) fetus serve as a model for long-gestation mammals such as sheep and human? This is particularly important for organs such as the lung and the kidney, whose development before birth is very much less in rodents than in the long-gestation species.

Animals↗
PubMed2005

The spiny mouse (Acomys cahirinus) completes nephrogenesis before birth.

The spiny mouse is relatively mature at birth. We hypothesized that like other organs, the kidney may be more developed in the spiny mouse at birth, than in other rodents. If nephrogenesis is complete before birth, the spiny mouse may provide an excellent model with which to study the effects of an altered intrauterine environment on renal development. Due to its desert adaptation, the spiny mouse may have a reduced cortex-to-medulla ratio but an equivalent total nephron number to the C57/BL mouse. Kidneys were collected from fetal and neonatal spiny mice and sectioned for gross examination of metanephric development. Kidneys were collected from adult spiny mice (10 wk of age), and glomerular number, volume, and cortex-to-medulla ratios were determined using unbiased stereology. Nephrogenesis is complete in spiny mouse kidneys before birth. Metanephrogenesis begins at approximately day 18, and by day 38 of a 40-day gestation, the nephrogenic zone is no longer present. Spiny mice have a significantly (P < 0.001) lower total nephron number compared with C57/BL mice, although the total glomerular volume is similar. The cortex-to-medulla ratio of the spiny mouse is significantly (P < 0.01) smaller. The spiny mouse is the first rodent species shown to complete nephrogenesis before birth. This makes it an attractive candidate for the study of fetal and neonatal kidney development and function. The reduced total nephron number and cortex-to-medulla ratio in the spiny mouse may contribute to its ability to highly concentrate its urine under stressful conditions (i.e., dehydration).

Algorithms↗
PubMed2005

Reduced renal reserve and increased cardiac output in adult female sheep uninephrectomized as fetuses.

BACKGROUND: Removal of one kidney during the period of nephrogenesis in the sheep leads to offspring with elevated blood pressure and reduced glomerular filtration rate (GFR) at 6 and 12 months of age. The mechanisms underlying the hypertension and the degree of renal impairment are not known. METHODS: Changes in GFR were measured in response to an infusion of amino acids and cardiac output was measured by thermal dilution in female offspring at 2 years of age in eight control (sham-operated) and seven animals that had been unilaterally nephrectomized at 100 days of gestation. RESULTS: Animals uninephrectomized as fetuses had significantly higher blood pressure (91 +/- 2 mm Hg) compared to control animals (86 +/- 2 mm Hg) (P < 0.05). Cardiac output was significantly higher in the uninephrectomized group (148 +/- 10 mL/kg/min) compared to the control group (124 +/- 6 mL/kg/min) (P < 0.05). Heart rate and stroke volume were similar in the two groups although both parameters tended to be higher in the uninephrectomized group. Uninephrectomized animals had a lower basal GFR (P < 0.05). An infusion of amino acids caused a significantly different response in GFR in the two groups (P < 0.01 between the groups) with the uninephrectomized animals having significantly lower GFRs during the infusion period. CONCLUSION: The increased blood pressure observed after fetal uninephrectomy is due to an increase in cardiac output. Thus, formation of a low number of nephrons in utero may predispose an individual to later renal failure and elevated blood pressure.

Amino Acids↗
PubMed2005

Fetal renal and blood pressure responses to steroid infusion after early prenatal treatment with dexamethasone.

Maternal infusion of dexamethasone for 48 h early in gestation results in upregulation of mRNA for mineralocorticoid and glucocorticoid (MR and GR) receptors and angiotensin II receptors in ovine fetal kidneys late in gestation. This study sought to determine whether dexamethasone exposure results in changes in renal function and blood pressure responsiveness to infused cortisol or aldosterone in the late-gestation fetus. Merino ewes carrying single fetuses were infused with isotonic saline (Sal; n = 9) or dexamethasone (Dex, 0.48 mg/h; n = 10) for 48 h between days 26 and 28 of gestation (term = 150 days). At 115-122 days, renal function and blood pressure were measured in fetuses during a 4-h infusion of saline, cortisol (100 microg/h), or aldosterone (5 microg/h). Infusions were given in random order at least 2 days apart. Basal blood pressure and renal function were similar in Sal and Dex groups and did not change over the course of saline infusion. Cortisol infusion caused similar increases in blood pressure, urine flow, and glomerular filtration rate (GFR) in the groups. Aldosterone infusion caused a significantly different GFR response between the groups [P(treatment x time) < 0.05], but increase in K excretion and decrease in Na-to-K ratio were similar in the groups. The similar results obtained with cortisol and aldosterone infusion suggest no increased renal functional maturity to those hormones after early prenatal dexamethasone exposure. This suggests that changes in mRNA for MR and GR in kidneys of dexamethasone-exposed fetuses do not result in functional differences and highlights the renin-angiotensin system, as reported previously, as more important in this model.

Aldosterone↗
PubMed2004

Expression of aquaporin 1 in human cardiac and skeletal muscle.

Aquaporins (AQPs) are a family of water channel proteins that assist in maintenance of the cellular osmotic environment and whole body fluid balance. Specialized organ-specific AQPs are important in physiologic and pathologic processes but little is known about AQPs in the human heart. AQP1 has been identified in rodent heart. We investigated the presence and localization of AQP1 in human heart and skeletal muscle using immunohistochemistry and confocal microscopy, western blot and reverse transcriptase-polymerase chain reaction. There was abundant AQP1 present in both cardiac and skeletal muscle. Immunohistochemistry revealed co-localization of AQP1 with vinculin, a t-tubule marker, and caveolin-3. No novel sequences bearing an NPA box motif common to other AQPs were identified in human heart using degenerative PCR analysis. We conclude that AQP1 is present in the human heart. AQP1 co-localizes with t-tubular and caveolar proteins. Cardiac AQPs may have a role during osmotic stresses including ischemia/reperfusion and cardiopulmonary bypass.

Adult↗
PubMed2003

Vasopressin receptor expression in the placenta.

The arginine vasopressin (AVP) type 1a receptor (V1a) is well known to mediate vasoconstriction. In pregnancy, blood flow in the placenta is crucial for sustaining normal growth and development of the fetus. This is the first AVP receptor study in the placenta and fetal membranes. The aim was to compare, quantitatively, the level of V1a gene expression with that of a known marker for vascularization, aquaporin 1 (AQP1). V1a and AQP1 gene expression did not correlate; placental V1a mRNA levels were significantly upregulated at 45 and 66+/-1 compared with 27, 100+/-4, and 140 days (term approximately 150 days). V1a mRNA levels were much lower in fetal membranes in which no significant difference across gestation was observed. In situ hybridization histochemistry localized V1a gene expression in the maternal component of the placenta similar to the receptor-binding studies using 125I-labeled [d(CH2)5, sarcosine7] vasopressin. No AVP gene expression was observed in the placenta and fetal membranes, which eliminates local AVP production. This increase in V1a expression at 45 and 66+/-1 days of gestation correlates with the period of maximal placental growth in the sheep and suggests that AVP and V1a receptors may play a hitherto unrecognized role in placental growth, differentiation, and/or function, particularly in the deleterious effects of heat stress, early in pregnancy, on fetal growth.

Allantoin↗
PubMed2003

Kidney development and the fetal programming of adult disease.

Recent evidence, from both epidemiological and animal experimental studies, suggest that the very first environment, the intrauterine, is extremely important in determining the future health of the individual. Genetic and 'lifestyle' factors impinge on, and can exacerbate, a 'programming' effect of an adverse fetal environment. In this review, we present compelling evidence to suggest that one of the major organs affected by an unfavourable prenatal environment is the kidney. Many of the factors that can affect fetal renal development (i.e. exposure to excess glucocorticoids, insufficient vitamin A, protein/calorie malnutrition (in rats) and alterations in the intrarenal renin angiotensinogen system), also produce hypertension in the adult animal. When nephron number is compromised during kidney development, maladaptive functional changes occur and can lead, eventually, to hypertension and/or renal disease. Surprisingly, it is during the very earliest stages of kidney development that the vulnerability to these effects occurs.

Animals↗
PubMed2002

Quantitation of the mRNA levels of Epo and EpoR in various tissues in the ovine fetus.

A partial cDNA of the sheep erythropoietin receptor (EpoR) was obtained and used in real-time PCR to quantitate mRNA levels in placenta, liver and kidney throughout development (term=150 days). This was compared with Epo mRNA levels in the same tissues. Both Epo and EpoR mRNA were present in the placenta throughout gestation at low levels from 66 days onwards and these did not vary throughout gestation. Compared with the expression levels in the placenta, the levels of EpoR gene expression in the liver at 66, 99 and 140 days were, median (range)-288 (120-343), 278 (63-541) and 7 (3-15), respectively, reflecting the disappearance of erythropoiesis after 130 days. Low levels of EpoR gene expression were seen in the kidney at 3 (2-5), 5 (2-7), and 7 (2-10) times that in the placenta at 66, 99, and 140 days, respectively. By hybridization histochemistry the EpoR mRNA was located in the proximal tubular cells of the mesonephros and metanephros at 42 days. Epo mRNA levels in the kidney were 215 (116-867), 528 (113-765) and 46 (15-204) times those in the placenta at 69, 99, and 140 days, respectively. In the liver at the same ages the concentrations of mRNA were lower than in the kidney, the liver/placenta ratios being 50 (11-90), 17 (3-39), 9 (5-14). At 130 days Epo/EpoR levels in the hippocampus were 6+/-3 and 8+/-3 times that in the term placenta, respectively. These studies demonstrate that the ovine placenta expresses the Epo gene from at least 66 days of gestation. However, gene expression levels are very low compared with those in the liver and kidney, and even the hippocampus.

Amino Acid Sequence↗
PubMed2002

Programmed hypertension: kidney, brain or both?

The results from numerous epidemiological studies suggested that there was a link between low birth weight (low for gestational age) and development of high blood pressure in adulthood. More recently, it has been shown that one important determinant is the early exposure of the developing fetus to excess glucocorticoid (GC). Hypertension develops in adult sheep and rats that are exposed to excess GC at a stage in gestation when both kidney and brain are still extremely primitive organs. Here, we propose that permanent changes in gene expression and function of these two organs could be crucial in the development of adult-onset hypertension as a result of prenatal GC exposure.

Adult↗
PubMed2002

Effect of early glucocorticoid treatment on MR and GR in late gestation ovine kidney.

BACKGROUND: The ontogeny of the renal mineralocorticoid (MR) and glucocorticoid (GR) receptors in the ovine fetus, and the effects of early exposure to synthetic or natural glucocorticoids on the expression of these genes in late gestation were examined. METHODS: A partial cDNA sequence for the ovine MR was cloned and used to generate primers and probes to measure MR mRNA expression by real-time polymerase chain reaction (PCR). GR mRNA was also measured. Kidneys were collected from ovine fetuses at various stages of gestation (days 60 to 140), twin ovine fetuses at 130 days, from ewes treated at days 26 to 28 with either saline, dexamethasone or cortisol, and adult sheep. Ligand binding was used to determine both GR and MR protein levels in all 130-day-old fetuses and adults. RESULTS: No significant changes in the expression of either renal MR or GR were detected throughout gestation. Cytosolic protein levels were higher in the fetal kidneys than in the adult. There was a significant increase in both fetal MR and GR mRNA expression, but not protein levels in kidneys from ewes pretreated with dexamethasone. CONCLUSIONS: MR and GR mRNA are expressed throughout development in ovine fetal kidneys. Dexamethasone treatment resulted in increased expression of MR and GR mRNA but not protein levels. The dissociation between fetal mRNA and protein levels, relative to adult kidneys, suggests that it may be confounding to draw conclusions based on mRNA levels alone.

Aldosterone↗
PubMed2002

Programming effects of short prenatal exposure to cortisol.

Recent studies have linked fetal exposure to a suboptimal intrauterine environment with adult hypertension. The aims of this study were twofold: 1) to see whether cortisol treatment administered to the ewe for 2 days at 27 days of gestation (term approximately 150 days) resulted in high blood pressure in offspring; 2) to study the effect of the same treatment on gene expression in the brain at 130 days of gestation and in lambs at 2 months of age. Mean arterial pressure was significantly higher in the adult female and male offspring of sheep treated with cortisol than in the control group (females: 89+/-2 mmHg vs. 81+/-2; P<0.05 and males: 102+/-4 mmHg vs. 91+/-3; P<0.05). Prenatal cortisol treatment led to up-regulation of angiotensinogen, AT1, MR, and GR mRNA in the hippocampus in fetuses at 130 days of gestation but not in the animals at 2 months of age. This is the first evidence that short prenatal exposure to cortisol programmed high blood pressure in the adult female and male offspring of sheep. Altered gene expression in the hippocampus could have a significant effect on the development of the hippocampus, and on postnatal behavior.

Animals↗
PubMed2002

Angiotensin II receptor (type 1 and 2) expression peaks when placental growth is maximal in sheep.

In sheep, placental size is maximal by midgestation, but blood flow continues to increase until term. No nerves are present and ANG II is thought to be a major regulator of vascular tone. We hypothesized that angiotensin type 2 receptors (AT(2)) would predominate over type 1 (AT(1)) until late in gestation and be primarily expressed in the vasculature. Real-time PCR, hybridization histochemistry, and ligand-binding studies were performed on placentae and fetal membranes at 27, 45, 66 +/- 1, 100 +/- 4, 130, and 140 days of gestation (term approximately 150 days) to determine quantitative changes and localization. The maximum level of AT(1) expression occurred in the 45-day placenta and was located predominantly in the maternal stromal cells. AT(1) receptors were expressed in the endothelial cells of the chorion in the first half of pregnancy, where later in gestation, both AT(1) and AT(2) receptors were predominant in blood vessels. These results suggest that ANG II, via the AT(1) receptor, may have hitherto unsuspected important roles in the growth/function on the ovine placenta during the maximal growth phase.

Animals↗