Sex-specific programming of hypertension in offspring of late-gestation diabetic rats

Katkhuda, Ragheed; Peterson, Emily; Roghair, Robert D.; Norris, Andrew W.; Scholz, Thomas; Segar, Jeffrey L.

doi:10.1038/pr.2012.93

Cited by 38 publications

(36 citation statements)

References 44 publications

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“…Sex-specific programming of high blood pressure following fetal insult is observed in many models of developmental programming (10, 11, 12, 22). Specifically, male offspring of late gestation diabetic dams (22), moderate protein restricted dams (11), and dams that undergo uteroplacental insufficiency via total ligation of the uterine vessels at day 18 gestation (10) or reduced uterine perfusion at day 14 gestation (12) exhibit a marked increase in blood pressure while female littermates remain normotensive.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, male offspring of late gestation diabetic dams (22), moderate protein restricted dams (11), and dams that undergo uteroplacental insufficiency via total ligation of the uterine vessels at day 18 gestation (10) or reduced uterine perfusion at day 14 gestation (12) exhibit a marked increase in blood pressure while female littermates remain normotensive. Previously our laboratory demonstrated a protective role for estradiol at four months of age against programmed increases in blood pressure in female growth-restricted offspring of reduced uterine perfusion dams (14).…”

Section: Discussionmentioning

confidence: 99%

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Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

et al. 2013

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Perinatal insults program sex differences in blood pressure, with males more susceptible than females. Aging may augment developmental programming of chronic disease, but the mechanisms involved are not clear. We previously reported that female growth-restricted offspring are normotensive after puberty. Therefore, we tested the hypothesis that age increases susceptibility to hypertension in female growth-restricted offspring. Blood pressure remained similar at 6 months of age; however, blood pressure was significantly elevated in female growth-restricted offspring relative to control by 12 months of age (137±3 versus 117±4 mmHg, P<0.01; respectively). Body weight did not differ at 6 or 12 months of age; however, total fat mass and visceral fat were significantly increased at 12 months in female growth-restricted offspring (P<0.05 versus control). Glomerular filtration rate remained normal, yet renal vascular resistance was increased at 12 months of age in female growth-restricted offspring (P<0.05 versus control). Plasma leptin, which can increase sympathetic nerve activity, did not differ at 6 months, but was increased at 12 months of age in female growth-restricted offspring (P<0.05 versus control). Due to the age-dependent increase in leptin, we hypothesized that the renal nerves may contribute to the age-dependent increase in blood pressure. Bilateral renal denervation abolished the elevated blood pressure in female growth-restricted offspring normalizing it relative to denervated female control offspring. Thus, these data indicate that age induces an increase in visceral fat and circulating leptin associated with a significant increase in blood pressure in female growth-restricted offspring with the renal nerves serving as an underlying mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

et al. 2013

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“…Additionally, the animals used in our study were all female. Hormonal differences between genders influence the effects of hyperglycemia (33). Likewise, PARP-1 is more neurotoxic in males than females (34).…”

Section: Discussionmentioning

confidence: 99%

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

et al. 2015

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Background: Hyperglycemia is a common metabolic problem in extremely low-birth-weight preterm infants. Neonatal hyperglycemia is associated with increased mortality and brain injury. Glucose-mediated oxidative injury may be responsible. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair and cell survival. However, PARP-1 overactivation leads to cell death. NF-κB is coactivated with PARP-1 and regulates microglial activation. The effects of recurrent hyperglycemia on PARP-1/NF-κB expression and microglial activation are not well understood. Methods: Rat pups were subjected to recurrent hypoinsulinemic hyperglycemia of 2 h duration twice daily from postnatal (P) day 3-P12 and killed on P13. mRNA and protein expression of PARP-1/NF-κB and their downstream effectors were determined in the cerebral cortex. Microgliosis was determined using CD11 immunohistochemistry. results: Recurrent hyperglycemia increased PARP-1 expression confined to the nucleus and without causing PARP-1 overactivation and cell death. NF-κB mRNA expression was increased, while IκB mRNA expression was decreased. inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expressions were decreased. Hyperglycemia significantly increased the number of microglia. conclusion: Recurrent hyperglycemia in neonatal rats is associated with upregulation of PARP-1 and NF-κB expression and subsequent microgliosis but not neuronal cell death in the cerebral cortex.

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“…Diabetes induced by injection of streptozotocin in late gestation in the rat programs hypertension in the male (91, 253) but not the female offspring (91). Renal function is impaired is association with hypertension in response to fetal exposure to maternal diabetes (140, 171).…”

Section: History and Etiology Of The Fetal Origins Of Cardiovascular DImentioning

confidence: 99%

Fetal Programming and Cardiovascular Pathology

Alexander

Dasinger

Intapad

2015

Comprehensive Physiology

183

144

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Low birth weight serves as a crude proxy for impaired growth during fetal life and indicates a failure for the fetus to achieve its full growth potential. Low birth weight can occur in response to numerous etiologies that include complications during pregnancy, poor prenatal care, parental smoking, maternal alcohol consumption or stress. Numerous epidemiological and experimental studies demonstrate that birth weight is inversely associated with blood pressure and coronary heart disease. Sex and age impact the developmental programming of hypertension. In addition, impaired growth during fetal life also programs enhanced vulnerability to a secondary insult. Macrosomia, which occurs in response to maternal obesity, diabetes and excessive weight gain during gestation, is also associated with increased cardiovascular risk. Yet, the exact mechanisms that permanently change the structure, physiology and endocrine health of an individual across their lifespan following altered growth during fetal life are not entirely clear. Transmission of increased risk from one generation to the next in the absence of an additional prenatal insult indicates an important role for epigenetic processes. Experimental studies also indicate that the sympathetic nervous system, the renin angiotensin system, increased production of oxidative stress and increased endothelin play an important role in the developmental programming of blood pressure in later life. Thus, this review will highlight how adverse influences during fetal life and early development program an increased risk for cardiovascular disease including high blood pressure and provide an overview of the underlying mechanisms that contribute to the fetal origins of cardiovascular pathology.

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Sex-specific programming of hypertension in offspring of late-gestation diabetic rats

Cited by 38 publications

References 44 publications

Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

Renal Denervation Abolishes the Age-Dependent Increase in Blood Pressure in Female Intrauterine Growth-Restricted Rats at 12 Months of Age

Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-κB expression and leads to microglial activation in the cerebral cortex

Fetal Programming and Cardiovascular Pathology

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