Iron transport and the kidney

Smith, Craig P.; Thévenod, Frank

doi:10.1016/j.bbagen.2008.10.010

Cited by 71 publications

(94 citation statements)

References 78 publications

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“…59 Fe-Tf was noted in the opposite direction in the absence or presence of PrP C , suggesting mainly unidirectional transport of iron from the glomerular filtrate to the kidney interstitium and increased kinetics of transport in the presence of PrP C . These observations are consistent with reports indicating the absence of major iron uptake proteins on the BL membrane of proximal and distal tubule cells, suggesting minimal uptake of iron from the blood stream (6,8). Notably, PrP ⌬51-89 had minimal effect on the uptake or transport of iron, highlighting the functional significance of FR activity of PrP C at this site.…”

Section: A-c) Prpsupporting

confidence: 81%

“…It was surprising to note that a significant amount of PrP C in PT cells was localized to recycling endosomes or late endosomes and lysosomes, a distribution markedly different from the mainly plasma membrane expression on neuronal cells (33,42,43). This can be explained by the large apical endocytosis activity of proximal tubule cells responsible in vivo for the uptake of a large daily load of small filtered proteins (6,8). The appearance of a post-translationally modified form of 59 Fe-Tf in the BL chamber of cells exposed to 59 Fe-citrate from the AP domain suggests that endocytic vesicles containing PrP C and 59 Fe intermix with BL vesicles containing apoTf-and Golgiderived vesicles, resulting in the generation of modified 59 Fe-Tf that migrates as a doublet on native gels.…”

Section: Discussionmentioning

confidence: 94%

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Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity

Haldar¹,

Tripathi²,

Qian³

et al. 2015

Journal of Biological Chemistry

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Section: A-c) Prpsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 94%

Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity

Haldar¹,

Tripathi²,

Qian³

et al. 2015

Journal of Biological Chemistry

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“…Emerging data, however, suggest that the kidney may be more extensively involved in iron metabolism than initially proposed. For instance, studies have revealed that multiple proteins involved in iron metabolism are expressed in the kidney, including hepcidin, FPN, and DMT-1 (43)(44)(45)(46)(47). Intriguingly, we found that deletion of FtH did not affect the expression of DMT-1 (expressed in late endosome/lysosome membranes of tubular cells), but was accompanied with diminution of FPN expression, in FtH PT-/-kidneys.…”

Section: Discussionmentioning

confidence: 52%

Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Zarjou¹,

Bolisetty²,

Joseph³

et al. 2013

J. Clin. Invest.

179

166

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Ferritin plays a central role in iron metabolism and is made of 24 subunits of 2 types: heavy chain and light chain. The ferritin heavy chain (FtH) has ferroxidase activity that is required for iron incorporation and limiting toxicity. The purpose of this study was to investigate the role of FtH in acute kidney injury (AKI) and renal iron handling by using proximal tubule-specific FtH-knockout mice (FtH PT-/-mice). FtH PT-/-mice had significant mortality, worse structural and functional renal injury, and increased levels of apoptosis in rhabdomyolysis and cisplatin-induced AKI, despite significantly higher expression of heme oxygenase-1, an antioxidant and cytoprotective enzyme. While expression of divalent metal transporter-1 was unaffected, expression of ferroportin (FPN) was significantly lower under both basal and rhabdomyolysis-induced AKI in FtH PT-/-mice. Apical localization of FPN was disrupted after AKI to a diffuse cytosolic and basolateral pattern. FtH, regardless of iron content and ferroxidase activity, induced FPN. Interestingly, urinary levels of the iron acceptor proteins neutrophil gelatinase-associated lipocalin, hemopexin, and transferrin were increased in FtH PT-/-mice after AKI. These results underscore the protective role of FtH and reveal the critical role of proximal tubule FtH in iron trafficking in AKI.

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“…The kidney may play an important role in systemic iron homeostasis. 37,38 The fact that large amounts of iron seem to be moving through lysosomal compartments of the kidney, 37 and that the 17-kD L-subunit band was highly expressed in kidney of ironoverloaded mice ( Figure 5A) has led us to hypothesize that the kidney may be an additional source of serum ferritin. By IF and TEM we detected ferritin in 2 locations of the proximal tubule cells.…”

Section: Macrophages Are a Major Cellular Source Of Serum Ferritinmentioning

confidence: 99%

“…37 The divalent metal transporter (DMT1) which is highly expressed in endosomes and lysosomes of proximal tubule cells may import the iron to the cytosol hence it can be exported to the blood stream by ferroportin. Alternatively, ferritin could export iron from these cells after loading near the apical brushborder of the proximal tubule cells, where a high accumulation of ferritin colocalizes with villin, an actin-binding protein involved in formation of microvilli in the intestine and the kidney ( Figure 7A).…”

Section: Cellular Source Of Serum Ferritinmentioning

confidence: 99%

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

Cohen

Gutiérrez

Weiss

et al. 2010

Blood

387

324

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The serum ferritin concentration is a clinical parameter measured widely for the differential diagnosis of anemia. Its levels increase with elevations of tissue iron stores and with inflammation, but studies on cellular sources of serum ferritin as well as its subunit composition, degree of iron loading and glycosylation have given rise to conflicting results. To gain further understanding of serum ferritin, we have used traditional and modern methodologies to characterize mouse serum ferritin. We find that both splenic macrophages and proximal tubule cells of the kidney are possible cellular sources for serum ferritin and that serum ferritin is secreted by cells rather than being the product of a cytosolic leak from damaged cells. Mouse serum ferritin is composed mostly of L-subunits, whereas it contains few H-subunits and iron content is low. L-subunits of serum ferritin are frequently truncated at the C-terminus, giving rise to a characteristic 17-kD band that has been previously observed in lysosomal ferritin. Taken together with the fact that mouse serum ferritin is not detectably glycosylated, we propose that mouse serum ferritin is secreted through the nonclassical lysosomal secretory pathway. (Blood. 2010;116(9):1574-1584) IntroductionFerritin in mammals is a mostly intracellular, cytosolic iron storage and detoxification protein. It consists of H-and L-subunits that assemble into a 24-subunit hollow sphere in which iron is sequestered. 1 However, ferritin can also be detected extracellularly, in cerebrospinal fluid and sinovial fluid. In serum it is an extracellular ferritin that has been used extensively in diagnostic tests. In the clinical setting, serum ferritin evaluation is most commonly used to estimate body iron stores as low serum ferritin correlates with iron depletion, whereas high serum ferritin correlates with elevated body iron stores or with inflammation in patients with normal body iron stores. 2,3 Characterization of serum ferritin has produced many controversial results regarding subunit composition, iron content and other features. It has been compared in some studies to the "natural apoferritin" fraction found in many tissues, which is essentially devoid of iron 4 while other studies have claimed that serum ferritin contains considerable amounts of iron. 5 In insects, ferritin is a secreted protein composed of 2 types of subunits and the heteropolymer functions most likely as an iron transporter in the hemolymph. Each of the subunits has a classical secretion signal and ferritin is secreted from the insect fat body. 6 In contrast, mammalian H-and L-ferritin subunits lack signals mediating endoplasmic reticulum (ER) targeting, but ferritin can traffic to the lysosomal compartment through autophagy. 7 Binding of human serum ferritin to the lectin Concanavalin A (ConA) has previously suggested that ferritin is glycosylated 8,9 and actively secreted through the ER-Golgi pathway. 10 Indeed, it was shown in hepatocyte cell-models that inhibition of ER-Golgi trafficking abolished secretion o...

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Iron transport and the kidney

Cited by 71 publications

References 78 publications

Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity

Prion Protein Promotes Kidney Iron Uptake via Its Ferrireductase Activity

Proximal tubule H-ferritin mediates iron trafficking in acute kidney injury

Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway

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