Prenatal Iron Deficiency Causes Fetal Kidney Hypoxia and Sex‐Dependent Upregulation of Cytochrome <i>c</i> Oxidase

Introduction Iron deficiency (ID) is the most prevalent nutritional deficiency worldwide, and affects populations across the socioeconomic spectrum. The incidence of ID anemia in pregnant women is of chief concern, with rates estimated to be 50–80% in developing countries, and 30% in western countries. Our group and others have shown that prenatal ID causes intrauterine growth restriction, to which the kidney is particularly vulnerable, although the precise mechanisms underlying the altered developmental and growth trajectories are unknown. Objective Here, we sought to determine whether prenatal ID causes fetal kidney hypoxia, cell death, and mitochondrial dysfunction, and whether such outcomes are sex‐specific. Methods Six and 12‐week old female rats (severe and moderate ID groups, respectively) were fed either a low iron (3 mg/kg diet) or iron‐replete (35 mg/kg diet) diet throughout pregnancy. Dams were treated with pimonidazole on gestational day (GD)20 to assess tissue hypoxia. Pregnant dams and fetuses were euthanized on GD21, and hematological indices of iron status were assessed. TUNEL was performed on fetal kidneys to assess apoptosis, and kidney morphology was assessed in stained tissue sections. Finally, high‐resolution respirometry was used to assess integrated mitochondrial function in fetal kidney homogenates. Results Maternal iron restriction resulted in 17% (P<0.01) and 48% reductions (P<0.001) in maternal hemoglobin (Hb) in the moderate (M‐ID) and severe (S‐ID) groups on GD21, respectively. While maternal plasma transferrin and ferritin levels were not altered in M‐ID, S‐ID maternal plasma ferritin decreased 75% (P<0.01) and plasma transferrin increased 25% (P<0.05). M‐ and S‐ID resulted in 39% and 65% decreases in fetal Hb (both P<0.001), which was accompanied by asymmetric fetal growth restriction, an effect more pronounced in the S‐ID group. Evidence of hypoxia was present in kidneys of both M‐ and S‐ID fetuses (both P<0.01). Female fetal kidneys in both M‐ and S‐ID groups exhibited upregulation of cytochrome c oxidase activity versus controls (both P<0.05), whereas males did not. Interestingly, S‐ID male kidneys exhibited increased apoptosis compared to controls (P=0.01), whereas females did not (P=0.86). Despite the above observations, no differences in glomerular size or density were observed in male or female S‐ID fetuses on GD21. Conclusions Both moderate and severe ID cause hypoxia and sex dependent upregulation of cytochrome c oxidase in fetal kidneys. Interestingly, fetal kidneys of ID females which upregulate cytochrome c oxidase do not become apoptotic like their male counterparts. These findings may provide insight into the sex‐specific programming of hypertension and renal dysfunction by prenatal ID. Support or Funding Information AW holds graduate studentships from Alberta Innovates Health Solutions (AIHS) and the Canadian Institutes of Health Research (CIHR); RM held a Heritage Youth Researcher Summer Studentship funded by AIHS; SB holds a CIHR New Investigator award. This work is supported by grants from CIHR and the Women and Children's Health Research Institute.

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