Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth.

Jones, Robert L.; Grady, Robert W.; Cerami, Anthony

doi:10.1084/jem.151.2.418

Cited by 37 publications

(29 citation statements)

References 10 publications

(8 reference statements)

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“…Early studies from the laboratories of J.A. Fernandez-Pol (59) and A. Cerami (60) suggested that low-molecular weight iron carriers were expressed by mammalian cells, but their identification was not established, nor were carrier proteins like Ngal implicated in their traffic. However, we found a factor in the mouse urine that was competitive with the bacterial siderophore.…”

Section: Discussionmentioning

confidence: 99%

“…The actions of endogenous Ngal in vivo might differ from its pharmacological effects, because the critical siderophore is a bacterial product. Low-molecular weight factors that transport iron, however, have been suggested by a variety of studies (59)(60)(61). These molecules may include citrate and related compounds, but also iron-transporting activities that have a molecular weight in the range of 1,000 Da.…”

Section: Ngal Upregulates Ho-1 In Atnmentioning

confidence: 99%

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Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Mori¹,

Lee²,

Rapoport³

et al. 2005

J. Clin. Invest.

217

238

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Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with ironbinding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules.In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 μg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngaldependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Ngal Upregulates Ho-1 In Atnmentioning

confidence: 99%

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Mori¹,

Lee²,

Rapoport³

et al. 2005

J. Clin. Invest.

217

238

View full text Add to dashboard Cite

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“…The missing data from this list are an identification of a mammalian homologue of the bacterial siderophore. However, there was a reddish low-molecular-weight substance in the initial steps of purification of 24p3/ NGAL, and there are older reports of low-molecularweight siderophores produced by mammalian cells (25,34,62).…”

Section: Hypothesis: 24p3/ngal Lipocalins Traffic Ironmentioning

confidence: 99%

“…Low-molecular-weight nontransferrin iron carriers have been partially purified but never clearly identified (25,34,62). Candidates include iron salts, such as iron ascorbate, citrate, or nitrilotriacetate, which display saturable uptake in cell lines (46,63,66,112).…”

Section: Many Solutions To the Problem Of Iron Transportmentioning

confidence: 99%

Iron, lipocalin, and kidney epithelia

Yang

Mori

et al. 2003

American Journal of Physiology-Renal Physiology

125

105

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Brilliant new discoveries in the field of iron metabolism have revealed novel transmembrane iron transporters, novel hormones that regulate iron traffic, and iron's control of gene expression. An important role for iron in the embryonic kidney was first identified by Ekblom, who studied transferrin (Landschulz W and Ekblom P. J Biol Chem 260: 15580-15584, 1985; Landschulz W, Thesleff I, and Ekblom P. J Cell Biol 98: 596-601, 1984; Thesleff I, Partanen AM, Landschulz W, Trowbridge IS, and Ekblom P. Differentiation 30: 152-158, 1985). Nevertheless, how iron traffics to developing organs remains obscure. This review discusses a member of the lipocalin superfamily, 24p3 or neutrophil gelatinase-associated lipocalcin (NGAL), which induces the formation of kidney epithelia. We review the data showing that lipocalins transport low-molecular-weight chemical signals and data indicating that 24p3/NGAL transports iron. We compare 24p3/NGAL to transferrin and a variety of other iron trafficking pathways and suggest specific roles for each in iron transport. metanephric mesenchyme; induction; neutrophil gelatinase-associated lipocalin; NGAL; 24p3; transferrin; embryo THE KIDNEY FORMS FROM THE interaction of an epithelial tubule called the ureteric bud and metanephric mesenchymal cells (103). The ureteric bud produces the collecting ducts, whereas the mesenchymal cells produce the glomeruli and tubules of the nephron. Mesenchymal cells convert into epithelia and form nephrons after receiving signals from the ureteric bud (15,29,42,44,61,71,103,106,115,116,119). The ureteric bud has been shown to control the growth of the mesenchyme (for example, by FGFs) (4, 92), the expression of the essential Wnt-4 gene (for example, by Wnt-6) (60), and the expression of cohorts of epithelial proteins [for example, by leukemia inhibitory factor (LIF)] (6, 95).In this review, we describe a new ureteric bud protein called 24p3 (mouse) or neutrophil gelatinase-associated lipocalcin (NGAL; human) and review its relatives in the lipocalin superfamily. 24p3/NGAL induces epithelial development, but it neither targets the same mesenchymal cells as Wnt-6/Wnt-4 or LIF, nor does it activate the same type of signaling mechanism. We hypothesize that 24p3/NGAL is a novel signaling molecule and iron transporter, and we speculate that it is a new member of the non-transferrin-bound iron pool (NTBI). We describe general mechanisms of iron transport and the settings in which 24p3/NGAL and the NTBI pool are active. Last, we compare iron transport in the developing and adult kidney. Iron metabolism in fetal development is topical: 18% of human pregnancies in the industrialized countries are iron deficient, as are 38-55% of pregnancies in Africa and 62-88% in India, and worldwide the total affected births may near one billion (14). However, because little is known about embryonic mechanisms of iron handling, we have included a number of hypotheses and suggested experiments. 24p3/NGAL INDUCES EPITHELIATo identify novel ureteric bud factors that activate the m...

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“…More than two decades ago, two groups (28,29) identified a 1500-Da iron-binding molecule from organs, blood, and urine, which was produced under iron-limiting conditions, bound to iron specifically and transferred iron into cells, indicating that it possesses the typical characteristics of a siderophore. Most interesting, one of the groups assayed the activity of this molecule with a bacterial growth assay, suggesting that the compound was highly related to a bacterial siderophore (29). In addition, recent experimental evidence indicates the presence of an NGAL binding partner in eukaryotic cells that mediates its iron-binding activity.…”

Section: Ngal-mediated Iron Delivery Induces Specific Cellular Responsesmentioning

confidence: 99%

Dual Action of Neutrophil Gelatinase–Associated Lipocalin

Schmidt‐Ott

Mori

et al. 2007

Journal of the American Society of Nephrology

693

609

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Neutrophil gelatinase-associated lipocalin (NGAL) is expressed and secreted by immune cells, hepatocytes, and renal tubular cells in various pathologic states. NGAL exerts bacteriostatic effects, which are explained by its ability to capture and deplete siderophores, small iron-binding molecules that are synthesized by certain bacteria as a means of iron acquisition. Consistently, NGAL deficiency in genetically modified mice leads to an increased growth of bacteria. However, growing evidence suggests effects of the protein beyond fighting microorganisms. NGAL acts as a growth and differentiation factor in multiple cell types, including developing and mature renal epithelia, and some of this activity is enhanced in the presence of siderophore:iron complexes. This has led to the hypothesis that eukaryotes might synthesize siderophore-like molecules that bind NGAL. Accordingly, NGAL-mediated iron shuttling between the extracellular and intracellular spaces may explain some of the biologic activities of the protein. Interest in NGAL has been sparked by the observation that NGAL is massively upregulated after renal tubular injury and may participate in limiting kidney damage. This review summarizes the current knowledge about the dual effects of NGAL as a siderophore:iron-binding protein and as a growth factor and examines the role of these effects in renal injury.

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Low molecular weight iron-binding factor from mammalian tissue that potentiates bacterial growth.

Cited by 37 publications

References 10 publications

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Iron, lipocalin, and kidney epithelia

Dual Action of Neutrophil Gelatinase–Associated Lipocalin

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