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Published on: July 3, 2013
Perinatal iron deficiency and a high salt diet cause long-term kidney mitochondrial dysfunction and oxidative stress
Andrew G Woodman1,2, Richard Mah1,2, Danae L Keddie1,2
1Department of Pharmacology, University of Alberta, Edmonton, Canada.
Insights
Perinatal iron deficiency (ID) programs male offspring for hypertension and kidney dysfunction, especially when combined with a high salt diet. These effects were not observed in female offspring, indicating a sex-dependent response.
Area of Science:
- Reproductive biology
- Developmental programming
- Cardiovascular physiology
Background:
- Perinatal iron deficiency (ID) is known to disrupt offspring development, leading to later-life cardiovascular issues.
- The specific mechanisms by which perinatal ID programs renal function and contributes to hypertension remain largely undefined.
- Sex-specific effects of perinatal ID on long-term health outcomes are increasingly recognized.
Purpose of the Study:
- To investigate whether perinatal iron deficiency (ID) induces hypertension and alters kidney metabolic function and morphology in adult offspring in a sex-dependent manner.
- To determine if chronic high salt intake exacerbates the effects of perinatal ID on renal function and blood pressure in offspring.
- To elucidate the underlying mechanisms, including mitochondrial dysfunction and oxidative stress, associated with perinatal ID and hypertension.
Main Methods:
- Pregnant rats were fed either iron-restricted or iron-replete diets.
- Adult offspring were exposed to normal or high salt diets before physiological assessments.
- Kidney mitochondrial function, reactive oxygen species, nitric oxide bioavailability, and renal morphology were evaluated.
- Blood pressure was measured in adult male and female offspring.
Main Results:
- Adult male offspring exposed to perinatal ID exhibited increased systolic blood pressure, particularly when combined with a high salt diet.
- Perinatal ID and/or high salt diet significantly altered kidney mitochondrial function, including reduced succinate-dependent respiration and complex IV activity in males.
- Male offspring showed increased oxidative stress markers (superoxide) and reduced nitric oxide bioavailability.
- Significant sex-dependent effects were observed, with female offspring showing no detrimental renal alterations.
Conclusions:
- Perinatal iron deficiency (ID) induces long-term, sex-dependent alterations in renal metabolic function and morphology in offspring.
- These programming effects, particularly in males, contribute to hypertension and may increase the risk of cardiovascular disease.
- Combined exposure to perinatal ID and high salt diet exacerbates these adverse renal and cardiovascular outcomes in male offspring.
Aims:
Perinatal iron deficiency (ID) alters developmental trajectories of offspring, predisposing them to cardiovascular dysfunction in later life. The mechanisms underlying this long-term programming of renal function have not been defined. We hypothesized perinatal ID causes hypertension and alters kidney metabolic function and morphology in a sex-dependent manner in adult offspring. Furthermore, we hypothesized these effects are exacerbated by chronic consumption of a high salt diet.
Methods And Results:
Pregnant Sprague Dawley rats were fed either an iron-restricted or replete diet prior to and throughout pregnancy. Adult offspring were fed normal or high salt diets for 6 weeks prior to experimentation at 6 months of age. Blood pressure (BP) was assessed via indwelling catheters in anaesthetized offspring; kidney mitochondrial function was assessed via high-resolution respirometry; reactive oxygen species and nitric oxide were quantified via fluorescence microscopy. Adult males, but not females, exhibited increased systolic BP due to ID (P = 0.01) and high salt intake (P = 0.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P = 0.003), while succinate-dependent respiration was reduced by ID (P < 0.05). The combination of perinatal ID and high salt reduced complex IV activity in the cortex of males (P = 0.01). Perinatal ID increased cytosolic superoxide generation (P < 0.001) concomitant with reduced nitric oxide bioavailability (P < 0.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P = 0.04) and cytosolic superoxide within the cortex (P = 0.01). Male offspring exhibited glomerular basement membrane thickening (P < 0.05), increased collagen deposition (P < 0.05), and glomerular hypertrophy (interaction, P = 0.02) due to both perinatal ID and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or ID.
Conclusion:
Perinatal ID causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.
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