A Switch in Iron Delivery Is Critical for Postnatal Kidney Development

Background: Periconceptual maternal iron deficiency (FeD) is a worldwide cause of premature births and low birth weights. Yet, it is unknown whether FeD affects all developing tissues equally, or rather targets s pecific lineages. In addition, since FeD restricts both transferrin bound and non-transferrin-bound (NTBI) iron species, their unique contributions to organogenesis are indeterminant. Methods: To address questions of iron traffic and kidney development, we examined the deletion of the singular transferrin receptor (TfR1 -/- ), created GFP-labeled TfR1 -/- ES cells for inoculation into wild blastocysts, and created TfR1-floxed mice to generate cell autonomous deletions of TfR1 in mesenchymal, ureteric, and stromal derivatives. Lastly, we created a model of global iron deficiency with iron poor diets, for comparison with cell autonomous TfR1 deletions. Results: Transferrin receptor deletions (TfD) only modestly suppressed tubulogenesis, had little, if any effect on the growth of the ureteric bud and no gross effects on kidney stroma at mid gestation. In contrast, nutritional iron deficiency nearly abolished kidney development, highlighting the limited phenotypes induced by TfD. Yet in the second postnatal week, the critical function of TfR1 became evident by the growth of residual TfR1 + cells that had escaped Cre-mediated deletion and by tubular segment specific polycystic transformation. Timed treatment with iron or systemic activators of iron trafficking prevented both cystic dysplasia and the terminal loss of kidney function, reversing extensive malformations of the kidney. Conclusion: TfR1 is the critical iron species targeting postnatal tubulogenesis, but in the embryo, TfR1 must be complemented by alternative iron species called NTBI. Iron deficient kidney disease is reversible postnatally.