Sex differences in prenatal programming of hypertension by dexamethasone

2021 ◽  
pp. 153537022110032
Author(s):  
Issa Alhamoud ◽  
Susan K Legan ◽  
Jyothsna Gattineni ◽  
Michel Baum
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Female Offspring ◽  
Male Offspring ◽  
Thick Ascending Limb ◽  
Protein Abundance ◽  
Female Rat ◽  
Prenatal Programming ◽  
Transporter Protein ◽  
Renal Tubular

Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.

scholarly journals Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance

2008 ◽  
Vol 295 (1) ◽  
pp. F29-F34 ◽  
Author(s):  
Amit Dagan ◽  
H. Moo Kwon ◽  
Vangipuram Dwarakanath ◽  
Michel Baum
Keyword(s):  
Blood Pressure ◽  
Renal Denervation ◽  
Control Group ◽  
Renal Nerves ◽  
Sham Operation ◽  
Protein Abundance ◽  
Prenatal Programming ◽  
Sham Operation Group ◽  
Renal Tubular ◽  
Type 3

Prenatal glucocorticoids are often administered to pregnant women to accelerate pulmonary maturation. We have demonstrated that administration of dexamethasone during specific periods of pregnancy in the rat causes hypertension in the offspring when they are studied as adults. The purpose of the present study was to determine whether the hypertension due to prenatal dexamethasone was mediated by renal nerves. We administered dexamethasone to rats daily for 4 days between days 15 and 18 of gestation. Rats underwent bilateral renal denervation or sham operation at 6 wk of age, and blood pressure was measured at 8 wk of age. Prenatal dexamethasone in the sham operation group resulted in an increase in blood pressure compared with vehicle-treated sham controls (134 ± 3 vs. 145 ± 3 mmHg, P < 0.05). Renal denervation did not affect blood pressure significantly in the prenatal vehicle-treated control group but resulted in normalization in blood pressure in the prenatal dexamethasone group and (130 ± 3 and 128 ± 5 mmHg, respectively). Prenatal dexamethasone increased type 3 Na+/H+ exchanger (NHE3), Na+-K+-2Cl− cotransporter (NKCC2), and Na+-Cl− cotransporter (NCC), but not α-, β-, and γ-epithelial Na+ channel (ENaC) protein abundance compared with controls. The increase in NHE3, NKCC2, and NCC protein abundance by prenatal dexamethasone was not seen in 8-wk-old rats 2 wk after renal denervation. Renal denervation did not affect NHE3, NKCC2, and NCC protein abundance in prenatal vehicle-treated animals. This study is consistent with renal nerves playing a role in mediating the hypertension by prenatal programming by dexamethasone.

Maternal dyslipidemia during pregnancy and lactation increases blood pressure and disrupts cardiorespiratory and glucose hemostasis in female rat offspring

2019 ◽  
Vol 44 (9) ◽  
pp. 925-936 ◽  
Author(s):  
Emmanuel Veríssimo de Araújo ◽  
Keyth Sulamitta de Lima Guimarães ◽  
Marciane Magnani ◽  
Josiane Campos Cruz ◽  
Hubert Vidal ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Disorders ◽  
Serum Levels ◽  
Female Offspring ◽  
Respiratory Pattern ◽  
Oral Glucose ◽  
Female Rat ◽  
Cardiorespiratory Control ◽  
Altered Glucose ◽  
Pregnancy And Lactation

Hypertension and metabolic disorders evidenced in adults who have been exposed to nutritional insults during early life may be sex-dependent. We evaluated if blood pressure (BP), cardiorespiratory control, and metabolic parameters are affected in female offspring (FO) from dams fed a dyslipidaemic diet during pregnancy and lactation. FO was obtained from dams who received control (CTL) or dyslipidaemic diets during pregnancy and lactation. The effects of a maternal dyslipidaemic diet on BP, cardiorespiratory control, and biochemical parameters were assessed at 30 and 90 days of age. The experimental protocol based on a dyslipidaemic diet intervention was effective in developing maternal dyslipidemia. At 30 days of age, the FO from dyslipidaemic dams displayed disordered respiratory pattern, enhanced ventilatory response to hypercapnia (P < 0.05), and increased serum levels of total cholesterol and triglycerides (P < 0.05) when compared with CTL female offspring. At 90 days of age, FO from dyslipidaemic dams had augmented BP (P < 0.05), exacerbated cardiorespiratory responses to hypercapnia (P < 0.05), enhanced pressor responses to peripheral chemoreflex activation (P < 0.05), impaired baroreflex (P < 0.05), and larger delta variations in arterial pressure after ganglionic blockade (P < 0.05). Furthermore, during oral glucose and insulin tolerance tests, FO from dyslipidaemic dams exhibited altered glucose tolerance and insulin sensitivity (P < 0.05) when compared with FO from CTL dams. Altered breathing linked to enhanced central and peripheral chemosensitivity, impaired baroreflex, and augmented sympathetic tone may be predisposing factors for increased BP and metabolic disorders in female offspring from dyslipidaemic dams.

scholarly journals Vascular nitric oxide and superoxide anion contribute to sex-specific programmed cardiovascular physiology in mice

2009 ◽  
Vol 296 (3) ◽  
pp. R651-R662 ◽  
Author(s):  
Robert D. Roghair ◽  
Jeffrey L. Segar ◽  
Kenneth A. Volk ◽  
Mark W. Chapleau ◽  
Lindsay M. Dallas ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Locomotor Activity ◽  
Nitric Oxide Synthase ◽  
Dietary Intervention ◽  
Female Offspring ◽  
High Salt ◽  
Male Offspring ◽  
Partial Substitution ◽  
Oxide Synthase

Intrauterine environmental pertubations have been linked to the development of adult hypertension. We sought to evaluate the interrelated roles of sex, nitric oxide, and reactive oxygen species (ROS) in programmed cardiovascular disease. Programming was induced in mice by maternal dietary intervention (DI; partial substitution of protein with carbohydrates and fat) or carbenoxolone administration (CX, to increase fetal glucocorticoid exposure). Adult blood pressure and locomotor activity were recorded by radiotelemetry at baseline, after a week of high salt, and after a week of high salt plus nitric oxide synthase inhibition (by l-NAME). In male offspring, DI or CX programmed an elevation in blood pressure that was exacerbated by Nω-nitro-l-arginine methyl ester administration, but not high salt alone. Mesenteric resistance vessels from DI male offspring displayed impaired vasorelaxation to ACh and nitroprusside, which was blocked by catalase and superoxide dismutase. CX-exposed females were normotensive, while DI females had nitric oxide synthase-dependent hypotension and enhanced mesenteric dilation. Despite the disparate cardiovascular phenotypes, both male and female DI offspring displayed increases in locomotor activity and aortic superoxide production. Despite dissimilar blood pressures, DI and CX-exposed females had reductions in cardiac baroreflex sensitivity. In conclusion, both maternal malnutrition and fetal glucocorticoid exposure program increases in arterial pressure in male but not female offspring. While maternal DI increased both superoxide-mediated vasoconstriction and nitric oxide mediated vasodilation, the balance of these factors favored the development of hypertension in males and hypotension in females.

scholarly journals Excess maternal salt or fructose intake programmes sex-specific, stress- and fructose-sensitive hypertension in the offspring

2015 ◽  
Vol 115 (4) ◽  
pp. 594-604 ◽  
Author(s):  
Clint Gray ◽  
Sheila M. Gardiner ◽  
Matthew Elmes ◽  
David S. Gardner
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Salt Intake ◽  
Maternal Diet ◽  
Cardiovascular Function ◽  
Female Offspring ◽  
Male Offspring ◽  
Pregnant Rats ◽  
Salt Loading ◽  
Male And Female

AbstractThe Western diet is typically high in salt and fructose, which have pressor activity. Maternal diet can affect offspring blood pressure, but the extent to which maternal intake of excess salt and fructose may influence cardiovascular function of the offspring is unknown. We sought to determine the effect of moderate maternal dietary intake of salt and/or fructose on resting and stimulated cardiovascular function of the adult male and female offspring. Pregnant rats were fed purified diets (±4 % salt) and water (±10 % fructose) before and during gestation and through lactation. Male and female offspring were weaned onto standard laboratory chow. From 9 to 14 weeks of age, cardiovascular parameters (basal, circadian and stimulated) were assessed continuously by radiotelemetry. Maternal salt intake rendered opposite-sex siblings with a 25-mmHg difference in blood pressure as adults; male offspring were hypertensive (15 mmHg mean arterial pressure (MAP)) and female offspring were hypotensive (10 mmHg MAP) above and below controls, respectively. Sex differences were unrelated to endothelial nitric oxide activity in vivo, but isolation-induced anxiety revealed a significantly steeper coupling between blood pressure and heart rate in salt-exposed male offspring but not in female offspring. MAP of all offspring was refractory to salt loading but sensitive to subsequent dietary fructose, an effect exacerbated in female offspring from fructose-fed dams. Circadian analyses of pressure in all offspring revealed higher mean set-point for heart rate and relative non-dipping of nocturnal pressure. In conclusion, increased salt and fructose in the maternal diet has lasting effects on offspring cardiovascular function that is sex-dependent and related to the offspring’s stress–response axis.

Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice

2007 ◽  
Vol 293 (4) ◽  
pp. F1314-F1324 ◽  
Author(s):  
Young Hee Kim ◽  
Vladimir Pech ◽  
Kathryn B. Spencer ◽  
William H. Beierwaltes ◽  
Lorraine A. Everett ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Protein Abundance ◽  
Lower Blood Pressure ◽  
Wild Type ◽  
Transporter Protein ◽  
Treatment Conditions ◽  
Lower Blood ◽  
Collecting Ducts ◽  
Transepithelial Voltage ◽  
And Function

Pendrin (encoded by Pds, Slc26a4) is a Cl−/HCO3− exchanger expressed in the apical regions of type B and non-A, non-B intercalated cells of kidney and mediates renal Cl− absorption, particularly when upregulated. Aldosterone increases blood pressure by increasing absorption of both Na+ and Cl− through increased protein abundance and function of Na+ transporters, such as the epithelial Na+ channel (ENaC) and the Na+-Cl− cotransporter (NCC), as well as Cl− transporters, such as pendrin. Because aldosterone analogs do not increase blood pressure in Slc26a4−/− mice, we asked whether Na+ excretion and Na+ transporter protein abundance are altered in kidneys from these mutant mice. Thus wild-type and Slc26a4-null mice were given a NaCl-replete, a NaCl-restricted, or NaCl-replete diet and aldosterone or aldosterone analogs. Abundance of the major renal Na+ transporters was examined with immunoblots and immunohistochemistry. Slc26a4-null mice showed an impaired ability to conserve Na+ during dietary NaCl restriction. Under treatment conditions in which circulating aldosterone is increased, α-, β-, and 85-kDa γ-ENaC subunit protein abundances were reduced 15–35%, whereas abundance of the 70-kDa fragment of γ-ENaC was reduced ∼70% in Slc26a4-null relative to wild-type mice. Moreover, ENaC-dependent changes in transepithelial voltage were much lower in cortical collecting ducts from Slc26a4-null than from wild-type mice. Thus, in kidney, ENaC protein abundance and function are modulated by pendrin or through a pendrin-dependent downstream event. The reduced ENaC protein abundance and function observed in Slc26a4-null mice contribute to their lower blood pressure and reduced ability to conserve Na+ during NaCl restriction.

RENAL TUBULAR ACIDOSIS, PRESENTING AS A SYNDROME RESEMBLING BARTTER'S SYNDROME, IN A PATIENT WITH ARACHNODACTYLY

1973 ◽  
Vol 73 (3) ◽  
pp. 531-542 ◽  
Author(s):  
Ryoyu Takeda ◽  
Shinpei Morimoto ◽  
Mitsuhiko Kuroda ◽  
Mototaka Murakami
Keyword(s):  
Blood Pressure ◽  
Renal Tubular Acidosis ◽  
Plasma Renin ◽  
Juxtaglomerular Apparatus ◽  
Renin Secretion ◽  
Marfan’S Syndrome ◽  
Marfan's Syndrome ◽  
Abrupt Decrease ◽  
Renal Tubular ◽  
High Level

ABSTRACT A 23-year-old man with Marfan's syndrome (forme fruste) and renal tubular acidosis presented a syndrome closely resembling that reported by Bartter et al. (1962), i.c., a markedly increased plasma renin activity (PRA), hypokalaemia with normal blood pressure, decreased response of blood pressure to angiotensin II infusion and hyperaldosteronism. Hyperplasia of the juxtaglomerular apparatus was seen on renal biopsy. The studies on renal tubular function demonstrated that the patient had a unique feature corresponding to a proximal type of renal tubular acidosis (RTA). During the period of sodium restriction the patient showed an abrupt decrease in sodium excretion to near or below intake levels with a tendency to potassium conservation but PRA remained unchanged. Sodiumloading did not suppress the increased level of PRA and albumin infusion showed only a little suppression of PRA. On the other hand, the oral administration of furosemide induced a significant increase in PRA. Replacement therapy with potassium induced a marked elevation of the urinary aldosterone level with a concomitant decrease in PRA when the serum potassium rose, but the PRA still remained above a level 10 times as high as the normal value. These findings suggested that the mechanism of renin secretion in this patient was reset at a high level. A hypothetical role of PRA in the reset mechanism of renin secretion and pathophysiology of this patient are discussed. The relationship between RTA and Marfan's syndrome remains obscure.

Abstract 014: Collecting Duct Specific Deletion of the (Pro)renin Receptor Modulates ENaC Expression

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Kai Song ◽  
Nikita Abraham ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Collecting Duct ◽  
Plasma Renin ◽  
Cre Recombinase ◽  
Protein Isoforms ◽  
Ang Ii ◽  
Renal Tubular ◽  
Renal Expression ◽  
Specific Deletion

The renal tubular (pro)renin receptor (PRR) has been shown to modulate water balance, blood pressure and Na + homeostasis. We recently reported that inducible nephron wide deletion of the PRR results in Na + wasting, reduced epithelial Na + channel (ENaC) expression in the kidney and attenuated hypertensive response to angiotensin-II (Ang-II) infusion. In this study, we examined the effects of PRR deletion in collecting duct (CD) specific mouse models targeting either the principal cells (PC) or intercalated cells (IC). PC-specific PRR knockout (KO) mice were obtained by crossing floxed PRR mice with mice harboring AQP-2 Cre recombinase. Compared to floxed mice, PC specific KO PRR mice had no differences in PRR immunostaining but had 50% reduction in PRR mRNA in micro-dissected cortical CDs. No differences in blood pressure were observed between the two groups at baseline or following Ang-II infusion at 600 ng/kg/min. Similarly, plasma renin concentration and renal expression of ENaC protein isoforms were comparable between the two groups. To achieve IC-specific PRR deletion, floxed PRR mice were bred with mice expressing B-1 Cre recombinase. Compared to floxed controls, IC-specific PRR KO mice were smaller (KO body weight: 5.9 ± 1.3 g vs controls: 11.1± 1.2 g) and did not survive beyond 30 days after birth. IC-specific PRR KO mice also demonstrated marked reduction in renal medullary PRR immunostaining along with decreased renal expression of ENaC-α protein (50% reduction compared to controls), similar to the findings in nephron wide deletion of PRR. Taken together, these findings suggest that IC specific deletion of PRR but not PC-specific deletion modulates renal ENaC expression. Further studies evaluating ENaC activity in isolated cortical CDs from PC and IC specific PRR KO mice will help delineate the functional role of CD PRR in Na + homeostasis.

scholarly journals Prenatal programming of rat thick ascending limb chloride transport by low-protein diet and dexamethasone

2009 ◽  
Vol 297 (1) ◽  
pp. R93-R99 ◽  
Author(s):  
Amit Dagan ◽  
Sabeen Habib ◽  
Jyothsna Gattineni ◽  
Vangipuram Dwarakanath ◽  
Michel Baum
Keyword(s):  
Blood Pressure ◽  
Sodium Transport ◽  
Chloride Transport ◽  
Protein Diet ◽  
Low Protein Diet ◽  
Control Group ◽  
Thick Ascending Limb ◽  
Prenatal Programming ◽  
Low Protein ◽  
Protein Group

Prenatal administration of dexamethasone and a low-protein diet has been shown to result in hypertension in the offspring when they are adults. The cause for the hypertension is unknown. The purpose of this study was to examine whether there was prenatal programming of thick ascending limb transport. Rats were administered either dexamethasone for 4 days (0.2 mg/kg body wt) by intraperitoneal injection daily between the 15th and 18th day of gestation, or they were fed a low-protein diet (6% protein) or an isocaloric normal protein diet (20% protein) from day 12 gestation until birth. The offspring were studied as adults. Prenatal dexamethasone and dietary protein deprivation resulted in an increase in blood pressure. Offspring of mothers fed a low-protein diet had an increase in medullary but not cortical bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) protein abundance ( P < 0.01). There was not a statistically significant increase in medullary NKCC2 by prenatal dexamethasone ( P = 0.07). Both prenatal administration of dexamethasone and a low-protein diet resulted in an increase in medullary thick ascending limb chloride transport compared with control (298 ± 33 pmoles·mm−1·min−1, 280 ± 26 pmoles·mm−1·min−1, and 191 ± 21 pmoles·mm−1·min−1, respectively P < 0.05). There was a higher lumen-positive transepithelial potential difference in the prenatal dexamethasone and low-protein group compared with control as well. Administration of furosemide for 24 h resulted in a decrease in blood pressure in the low-protein group but not the control group. This study demonstrates that insults administered to the fetus can program altered sodium transport. Increased tubular sodium transport is a likely cause for the hypertension by prenatal programming.

scholarly journals Renal tubular epithelial cell prorenin receptor regulates blood pressure and sodium transport

2016 ◽  
Vol 311 (1) ◽  
pp. F186-F194 ◽  
Author(s):  
Nirupama Ramkumar ◽  
Deborah Stuart ◽  
Elena Mironova ◽  
Vladislav Bugay ◽  
Shuping Wang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Renin ◽  
Tubular Epithelial Cell ◽  
Ang Ii ◽  
Developmental Abnormalities ◽  
Signaling Mechanisms ◽  
Prorenin Receptor ◽  
Collecting Ducts ◽  
Renal Tubular

The physiological significance of the renal tubular prorenin receptor (PRR) has been difficult to elucidate due to developmental abnormalities associated with global or renal-specific PRR knockout (KO). We recently developed an inducible renal tubule-wide PRR KO using the Pax8/LC1 transgenes and demonstrated that disruption of renal tubular PRR at 1 mo of age caused no renal histological abnormalities. Here, we examined the role of renal tubular PRR in blood pressure (BP) regulation and Na+ excretion and investigated the signaling mechanisms by which PRR regulates Na+ balance. No detectable differences in BP were observed between control and PRR KO mice fed normal- or low-Na+ diets. However, compared with controls, PRR KO mice had elevated plasma renin concentration and lower cumulative Na+ balance with normal- and low-Na+ intake. PRR KO mice had an attenuated hypertensive response and reduced Na+ retention following angiotensin II (ANG II) infusion. Furthermore, PRR KO mice had significantly lower epithelial Na+ channel (ENaC-α) expression. Treatment with mouse prorenin increased, while PRR antagonism decreased, ENaC activity in isolated split-open collecting ducts (CD). The prorenin effect was prevented by protein kinase A and Akt inhibition, but unaffected by blockade of AT1, ERK1/2, or p38 MAPK pathways. Taken together, these data indicate that renal tubular PRR, likely via direct prorenin/renin stimulation of PKA/Akt-dependent pathways, stimulates CD ENaC activity. Absence of renal tubular PRR promotes Na+ wasting and reduces the hypertensive response to ANG II.

scholarly journals Sex-specific effects of advanced maternal age on cardiovascular function in aged adult rat offspring

2018 ◽  
Vol 315 (6) ◽  
pp. H1724-H1734 ◽  
Author(s):  
Amin Shah ◽  
Christy-Lynn M. Cooke ◽  
Raven D. Kirschenman ◽  
Anita L. Quon ◽  
Jude S. Morton ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Reperfusion Injury ◽  
Young Adulthood ◽  
Maternal Age ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiovascular Function ◽  
Advanced Maternal Age ◽  
Female Offspring ◽  
Male Offspring

Pregnancy at an advanced maternal age has an increased risk of complications for both the mothers and their offspring. We have previously shown that advanced maternal age in a rat model leads to poor fetal outcomes, maternal vascular dysfunction, and hypertension, concordant with findings in humans. Moreover, offspring from aged dams had sex-specific cardiovascular dysfunction in young adulthood. However, the detrimental impact of aging on the cardiovascular system of the offspring in this model is unknown. We hypothesized that offspring born to aged dams (9.5–10 mo old) would have impaired cardiovascular function at 12 mo of age. Echocardiographic data revealed signs of mild left ventricular diastolic dysfunction in only male offspring from aged dams [isovolumetric relaxation time: 34.27 ± 2.04 in the young dam group vs. 27.61 ± 0.99 ms in the aged dam group, P < 0.01; mitral annular velocity ratio ( E′/ A′): 1.08 ± 0.04 in the young dam group vs. 0.96 ± 0.02 in the aged dam group, P < 0.05]. We have previously shown that in young adulthood (4 mo of age), male, but not female, offspring born to aged dams had impaired recovery from ischemia-reperfusion injury. Aging did not alter the susceptibility of female offspring to ischemia-reperfusion injury. Interestingly, wire myography data revealed that male offspring from aged dams had enhanced vascular sensitivity to methacholine (negative log of EC50: 7.4 ± 0.08 in young dams vs. 7.9 ± 0.11 in aged dams, P = 0.007) due, in part, to increased prostaglandin-mediated vasodilation. Despite intact endothelium-dependent relaxation, female offspring from aged dams had elevated systolic blood pressure (125.3 ± 4.2 mmHg in young dams vs. 144.0 ± 6.9 mmHg in aged dams, P = 0.03). These data highlight sex-specific mechanisms underlying cardiovascular programming in offspring born to dams of advanced age. NEW & NOTEWORTHY Our study demonstrated that adult male and female offspring (12 mo old) born to aged dams had impaired cardiac diastolic function and increased blood pressure, respectively, signifying sex-specific differential cardiovascular effects of advanced maternal age.

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