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The Impact of Perinatal Iron Deficiency on Renal Development and Long-Term Cardiovascular Function in Rats
- Author / Creator
- Woodman, Andrew G
Stressors that occur in early development can affect long-term health and resilience. Iron deficiency (ID) is one of the most common nutritional deficiencies worldwide, and is an epidemic among pregnant women and young children. Perinatal ID is associated with neonatal morbidity and mortality, but may also predisposing offspring for cardiovascular dysfunction in later life. However, the mechanisms through which this long-term programming of cardiovascular dysfunction occurs have not been fully elucidated. Here, we interrogated the mechanisms through which perinatal ID affects offspring cardiovascular development, and in turn affects long-term cardiovascular health.
Female Sprague Dawley rats were fed either an iron restricted (3 or 10 mg/kg ferric citrate) or iron replete (37 mg/kg ferric citrate) purified diet prior to and throughout gestation; dams were fed an iron-replete diet at birth. Offspring were studied either at the end of gestation, in the neonatal period (postnatal days 1-28), or in adulthood.
At gestational day 21, maternal iron restriction resulted in fetal anemia and asymmetric growth restriction, as well as organ-specific patterns of hypoxia, such that kidneys and livers were affected, whereas the brains and placentae of offspring remained normoxic. Prenatal ID caused mitochondrial dysfunction and increased reactive oxygen species generation in the livers and kidneys, albeit the effects were much more pronounced in the kidneys of male offspring, whereas females were largely spared.
In neonates, perinatal ID reduced nephron endowment of male but not female offspring. Perinatal ID caused dysregulated vitamin A metabolism, especially in male offspring, along with other nephrogenic signaling pathways. Additionally, perinatal ID resulted in alterations in cellular senescence, apoptosis, autophagy, and oxidative stress, implicating these as potential mechanisms for impaired nephrogenesis.
In adult offspring, males exposed to perinatal ID exhibited salt sensitive hypertension and vascular dysfunction, characterized by deficiencies in nitric oxide bioavailability, likely secondary to enhanced oxidative stress. Indeed, adult male perinatal ID offspring exhibit increased renal reactive oxygen species generation concomitant with impaired mitochondrial respiration. A high salt diet in adulthood exacerbated renal injury in male perinatal ID offspring, resulting in glomerular hypertrophy and injury; these effects were not observed in adult females.
In summary, the studies herein provide mechanistic insights into how perinatal ID affects long-term cardiovascular function. Given the high incidence of ID in pregnant women, the developmental programming effects stemming from ID could have substantial implications on the global burden of cardiovascular and kidney disease.
- Graduation date
- Fall 2021
- Type of Item
- Doctor of Philosophy
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