Perinatal iron deficiency and a high salt diet cause long-term kidney mitochondrial dysfunction and oxidative stress

Abstract

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.