GSE100251
A Switch in Iron Transport Mechanisms Defines Novel Forms of Congenital Chronic Kidney Disease [P13 Tfr1KO;Six2Cre]
Periconceptual maternal iron deficiency (FeD) is a worldwide problem resulting in prematurity and low birth weights. Yet, it is not known whether FeD affects all developing tissues, or rather targets specific lineages. To address these questions, we investigated the targeting of the kidney by FeD. We found that FeD reduced both serum transferrin-iron and non-transferrin-bound-iron (NTBI), and these deficiencies targeted the renal proximal nephron rather than renal collecting ducts or stroma. In contrast, proximal tubular deletions of TfR1 (TfD) caused only modest defects in kidney development implying compensation by NTBI in the embryo. Yet, after the first two postnatal weeks, proximal TfD resulted in striking segmentally specific hypoplasia, as well as well as pervasive cystic transformation with Bardet-Biedel or Nephronothesis protein deficiencies. Treatment with NTBI as well as systemic activators of HIF which induce iron trafficking bypassed TfD and rescued the cystic disease and suppressed kidney damage. In sum, iron depletion resulted in new forms of chronic kidney disease. Its phenotype resulted from the alternative use of two different forms of iron, NTBI and Tf-iron at different stages and in different cells of the developing kidney. Overall design: Examining the transcriptional profile of conditional Tfr1 knockout (Six2Cre) in the mouse kidney compared to control at post-natal day 13.  n=3 biological replicates, respectively.