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

Abstract

Aims\nPerinatal iron deficiency 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 iron deficiency 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.\n\n\nMethods and Results\nPregnant 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 six weeks prior to experimentation at six months of age. Blood pressure was assessed via indwelling catheters in anesthetized 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 blood pressure due to iron deficiency (P\u2009=\u20090.01) and high salt intake (P\u2009=\u20090.02). In males, but not in females, medullary mitochondrial content was increased by high salt (P\u2009=\u20090.003), while succinate-dependent respiration was reduced by iron deficiency (P\u2009<\u20090.05). The combination of perinatal iron deficiency and high salt reduced complex IV activity in the cortex of males (P\u2009=\u20090.01). Perinatal iron deficiency increased cytosolic superoxide generation (P\u2009<\u20090.001) concomitant with reduced nitric oxide bioavailability (P\u2009<\u20090.001) in male offspring, while high salt increased mitochondrial superoxide in the medulla (P\u2009=\u20090.04) and cytosolic superoxide within the cortex (P\u2009=\u20090.01). Male offspring exhibited glomerular basement membrane thickening (P\u2009<\u20090.05), increased collagen deposition (P\u2009<\u20090.05), and glomerular hypertrophy (interaction, P\u2009=\u20090.02) due to both perinatal iron deficiency and high salt. Female offspring exhibited no alterations in mitochondrial function or morphology due to either high salt or iron deficiency.\n\n\nConclusions\nPerinatal iron deficiency causes long-term sex-dependent alterations in renal metabolic function and morphology, potentially contributing to hypertension and increased cardiovascular disease risk.