In pregnant women, iron deficiency increases the risk for a preterm delivery and delivering a low birth weight baby, which highlights the importance to understand how the required quantity of iron is delivered to the developing embryo for organogenesis and the prevention of defects. Iron is required for the optimal growth of the kidney during pregnancy and the early postnatal period, and iron deficiency reduces nephron number and results in hypertension and hypoplasia. The need for iron occurs throughout kidney morphogenesis, including the conversion of the metanephric mesenchyme into epithelia, the branching of the ureteric bud, and the postnatal completion of glomerulogenesis. The complexity of iron is due to its complete insolubility and toxicity, which accounts for its unavailability in many diets, and for the ongoing difficulties of medicating >100 million iron deficient human pregnancies in all parts of the world. These data implicate complex and highly regulated mechanisms that synchronize cell need with the capture of iron. Studies in professional iron trafficking cells have revealed the molecular mechanisms underlying the iron cycle, but deletion of its main components (transferring, transferrin receptor 1[Tfr1] or divalent metal transporter 1[DMT1]) has produced a much more limited phenotype than predicted by the ubiquity of these proteins or their conservation among species. Do mechanisms found in the adult even apply to developing organs? Does the ureteric bud and mesenchyme obtain iron from different sources, or is there a single source of iron for all compartments? Does iron enter these cells by a common or multiple pathway(s), or are there cell type and stage specific mechanisms of iron capture? Is iron delivery cell autonomous or does reciprocal induction also include the exchange of iron between compartments in order to synchronize their mutual development? What is the consequence of deleting a ubiquitous iron delivery pathway Tf-Tfr1: is one compartment of the kidney more affected than the other? Iron delivery and iron utility in organogenesis is currently a black box . In this proposal, we identify processes that induce renal growth by evaluating the central iron delivery pathway, Tf-Tfr1. The initial data were surprising this pathway is not the global iron donor in the initiation of kidney, but is critically required for the advance of kidney development. We consequently demonstrate that iron transport is temporally cell specific and we define novel molecular components based on both transferrin and non-transferrin pathways of iron delivery. This work generates a map of an essential factor in kidney development and it explains the mechanisms of iron deficient kidney hypoplasia.
The strategies and approaches outlined in this proposal aim to dissect the iron delivery pathways in the developing kidney in a cell- and time- specific fashion. While iron deficiency in pregnant women leads to increased risk for preterm delivery and delivering low-birth babies with kidney hypoplasia, this study will lead to better understanding of how the required quantity of iron is delivered to different compartments of the developing kidney for optimal organogenesis. Further, this study will allow us to model the pathogenesis of human kidney hypoplasia caused by iron deficiency in mice for developing its optimal prevention.
