Iron deficiency in pregnancy is the most common micronutrient deficiency in the world, affecting as many as 2 billion people. Iron deficiency in pregnancy increases the risk for embryonic mortality, a preterm delivery and low birth weight baby, which highlights the importance of understanding how the required quantity of iron is delivered to the embryo for the prevention of birth defects. The developing kidney requires sufficient iron for optimal organogenesis during pregnancy and in the early postnatal period. Iron is required throughout kidney morphogenesis, including during conversion of the metanephric mesenchyme into epithelia, during the branching of the ureteric bud, and during the postnatal completion of glomerulogenesis. Iron deficiency reduces nephron number and results in hypoplasia and hypertension, which increases the risk of renal failure and cardiovascular diseases in adult life. However, the mechanism by which iron traffics from the placenta to different cell lineages in developing organs including kidney has been a """"""""black box"""""""" and as a result there have been few advances and almost no literature in understanding the impact of iron deficiency on organogenesis. The current paradigm of iron trafficking derives from studies in the adult. These studies have revealed the molecular mechanisms underlying the so-called iron cycle, but surprisingly the deletion of its main components (transferring, transferring receptor1[Tfr1], divalent metal transporter 1[DMT1], Steap3, TIM) has produced much more limited phenotypes in the embryos than might have been predicted by the ubiquity of these proteins, and their conservation among species. Hence it remains unclear whether the ureteric bud and mesenchyme in the developing kidney obtain iron from different sources, whether iron delivery is """"""""cell autonomous"""""""" or does reciprocal induction also include the exchange of iron between compartments, and whether iron deficiency dysregulates organogenesis of different cell lineages differently? In this proposal, we identify iron trafficking processes that induce real growth and development by genetically dissecting the functions of the central iron delivery pathway, Tf-Tfr1, in the developing kidney. The initial data unexpectedly suggested the following hypotheses, which we test here: these are (1) a cell specific, and (2) a temporally specific requirement for Tf-Tfr1, (3) a classical cell autonomous mechanism mediated by Tfr1, but additionally the possibility of a cell non-autonomous pathway as well, (4) the activity of non-Tf iron donors, including a novel pathway involving ferritin and (5) the activity of a unique iron transporter that is both sufficient and necessary to transfer Tf iron to the cytosol of the developing kidney. These hypotheses identify and test novel, tissue specific, and stage specific mechanisms of iron delivery, implicating that complex and highly regulated mechanisms synchronize cell need with iron capture. We suggest that these pathways are likely to be the target of iron deficiency in pregnancy, which is known to limit kidney growth and development.

Public Health Relevance

Pregnancy triples the nutritional requirement for iron, threatening the success of pregnancy in millions of women. Iron deficiency limits the growth of the kidney, but mechanisms of iron acquisition critical in organ development have not been resolved. We plan a systematic analysis that starts with the central components of the pathway, Tf-Tfr1, but also tests novel and critical genes which traffic iron in embryo. Our study will identfy the pathways that deliver the required quantity of iron to the developing kidney for optimal organogenesis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Hoshizaki, Deborah K
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Wang, Xueqiao; Zheng, Xiaoqing; Zhang, Juanlian et al. (2018) Physiological functions of ferroportin in the regulation of renal iron recycling and ischemic acute kidney injury. Am J Physiol Renal Physiol 315:F1042-F1057
Kiryluk, Krzysztof; Bomback, Andrew S; Cheng, Yim-Ling et al. (2018) Precision Medicine for Acute Kidney Injury (AKI): Redefining AKI by Agnostic Kidney Tissue Interrogation and Genetics. Semin Nephrol 38:40-51
Park, Jihwan; Shrestha, Rojesh; Qiu, Chengxiang et al. (2018) Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360:758-763
Werth, Max; Schmidt-Ott, Kai M; Leete, Thomas et al. (2017) Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts. Elife 6:
Xu, Katherine; Rosenstiel, Paul; Paragas, Neal et al. (2017) Unique Transcriptional Programs Identify Subtypes of AKI. J Am Soc Nephrol 28:1729-1740
Barasch, Jonathan; Hollmen, Maria; Deng, Rong et al. (2016) Disposal of iron by a mutant form of lipocalin 2. Nat Commun 7:12973
Bao, Guan-Hu; Ho, Chi-Tang; Barasch, Jonathan (2015) The Ligands of Neutrophil Gelatinase-Associated Lipocalin. RSC Adv 5:104363-104374
Bao, Guan-Hu; Barasch, Jonathan; Xu, Jie et al. (2015) Purification and Structural Characterization of ""Simple Catechol"", the NGAL-Siderocalin Siderophore in Human Urine. RSC Adv 5:28527-28535
Paragas, Neal; Kulkarni, Ritwij; Werth, Max et al. (2014) ?-Intercalated cells defend the urinary system from bacterial infection. J Clin Invest 124:2963-76
Bao, Guan-Hu; Xu, Jie; Hu, Feng-Lin et al. (2013) EGCG inhibit chemical reactivity of iron through forming an Ngal-EGCG-iron complex. Biometals 26:1041-50