Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function

Hubert, Nadia; Hentze, Matthias W.

doi:10.1073/pnas.192423399

Cited by 376 publications

(346 citation statements)

References 32 publications

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“…Along the terminal nephron segments, Zn 2ϩ inhibited Cd 2ϩ transport and vice versa, suggesting that DMT1 may play an important role in Zn 2ϩ reabsorption in this part of the nephron. Interestingly, four DMT1 isoforms have been identified in renal tissue (19). Thus the difference between the effects of Zn 2ϩ action on Cd 2ϩ uptake in the LH and more distal segments could be due to the pattern of expression of these different isoforms (33).…”

Section: Discussionmentioning

confidence: 99%

Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo

Barbier¹,

Jacquillet²,

Tauc³

et al. 2004

American Journal of Physiology-Renal Physiology

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Barbier, O., G. Jacquillet, M. Tauc, P. Poujeol, and M. Cougnon. Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo. Am J Physiol Renal Physiol 287: F1067-F1075, 2004. First published July 27, 2004 doi:10.1152/ajprenal.00120.2004.-This study investigates the effect in rats of acute CdCl2 (5 M) intoxication on renal function and characterizes the transport of Ca 2ϩ , Cd 2ϩ , and Zn 2ϩ in the proximal tubule (PT), loop of Henle (LH), and terminal segments of the nephron (DT) using whole kidney clearance and nephron microinjection techniques. Acute Cd 2ϩ injection resulted in renal losses of Na ϩ , K ϩ , Ca 2ϩ , Mg 2ϩ , PO 4 Ϫ2 , and water, but the glomerular filtration rate remained stable. 45 Ca microinjections showed that Ca 2ϩ permeability in the DT was strongly inhibited by Cd 2ϩ (20 M), Gd 3ϩ (100 M), and La 3ϩ (1 mM), whereas nifedipine (20 M) had no effect. 109 Cd and 65 Zn 2ϩ microinjections showed that each segment of nephron was permeable to these metals. In the PT, 95% of injected amounts of 109 Cd were taken up. 109 Cd fluxes were inhibited by Gd 3ϩ (90 M), Co 2ϩ (100 M), and Fe 2ϩ (100 M) in all nephron segments. Bumetanide (50 M) only inhibited 109 Cd fluxes in LH; Zn 2ϩ (50 and 500 M) inhibited transport of 109 Cd in DT. In conclusion, these results indicate that 1) the renal effects of acute Cd 2ϩ intoxication are suggestive of proximal tubulopathy; 2) Cd 2ϩ inhibits Ca 2ϩ reabsorption possibly through the epithelial Ca 2ϩ channel in the DT, and this blockade could account for the hypercalciuria associated with Cd 2ϩ intoxication; 3) the PT is the major site of Cd 2ϩ reabsorption; 4) the paracellular pathway and DMT1 could be involved in Cd 2ϩ reabsorption along the LH; 5) DMT1 may be one of the major transporters of Cd 2ϩ in the DT; and 6) Zn 2ϩ is taken up along each part of the nephron and its transport in the terminal segments could occur via DMT1. heavy metals; epithelial calcium channel; divalent metal transporter 1; kidney CADMIUM (CD 2ϩ ) IS ONE OF THE most commonly found toxic metals present in our environment. The major sources of exposure to Cd 2ϩ are contaminated food and water, tobacco, and industrial fumes and dusts (16). Cd 2ϩ accumulates in the body, and chronic exposure causes severe nephrotoxicity in humans (16) and animals (2, 4). The renal dysfunction may be due to proximal tubular damage affecting the passive paracellular pathway (14, 27) and decreasing active transcellular ion transport (30). With the use of in vitro models, deleterious effects of Cd 2ϩ have been described on several solute transporters, such as stretch-activated ion channels (24), the epithelial Ca 2ϩ channel (ECaC) transporter (32), the NaPi-II transporter (19), the Na/glucose transporter (1), and the NaSi-1 transporter (25). These acute effects of Cd 2ϩ suggest the involvement of ion transporters in Cd 2ϩ -induced nephropathy. Therefore, the question arises as to whether these transporters are affected in vivo after Cd 2ϩ exposure. To answer this question,...

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Section: Discussionmentioning

confidence: 99%

Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo

Barbier¹,

Jacquillet²,

Tauc³

et al. 2004

American Journal of Physiology-Renal Physiology

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“…is outside the variants alternative isoforms recently described as tissue-specific [9] and is common to human and closely analogous in rat. This sequence is located in the presumed extracellular portion between transmembrane loops 7 and 8.…”

Section: Materials and Methods Antibodiesmentioning

confidence: 96%

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

et al. 2003

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There are two pathways for inorganic iron uptake in the intestine, the ferric pathway, mediated by the key protein mobilferrin, and the ferrous pathway, mediated by DMT-1. Previous studies reported that the amount of DMT-1 increased in the intestinal mucosa in iron deficiency and the increase was seen in the apical portion of the villus of the duodenal mucosa. Mobilferrin did not quantitatively increase but became localized at the cell membrane. However, studies on fresh tissue have not previously been performed and the localization to the microvillae has not been demonstrated. In order to more definitively localize these proteins immunofluorescent and electron microscopic studies were undertaken. Samples were also subjected to biochemical analysis and Western analysis. In iron-deficient animals both DMT-1 and Mobilferrin were concentrated in the apical surface of the villae. Electron microscopy revealed that the majority of this increase in the amount of these proteins near the luminal surface was due to increased binding of the proteins to mucin in vesicles near the surface. A significant portion of the iron transport proteins was localized in the goblet cells and outside the cell in the luminal mucin, as demonstrated by immunofluorescence, electron microscopy, and isolation of the mucin by cesium chloride gradient centrifugation and Western analysis. A new model for the transport of metal ions was suggested. The metal transport proteins travel from vesicles inside the cell out to the lumen mucin. This increases the surface area and allows a greater portion of the lumen contents to be exposed to the binding proteins. Once the metal is bound to the externalized protein it is internalized into the cell. This explains many of the unique properties of the iron-binding proteins and suggests that it may be a more general model for the absorption of other nutrients. Am. J. Hematol. 74:32-45, 2003.

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“…21 Because the primers used in the quantitative PCR are expected to recognize all four isoforms, we performed semiquantitative RT-PCR using isoform-specific primers to determine whether expression of DMT1 isoforms is altered in cirrhotic liver. Both the IRE and non-IRE DMT1 isoforms were present in control and cirrhotic livers, and the IRE-containing transcript remained detectable in cirrhotic livers with elevated iron concentrations ( Figure 5).…”

Section: Hepatic Expression Of Genes and Proteins Involved In Iron Mementioning

confidence: 99%

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

Bergmann

Mathahs

Broadhurst

et al. 2008

Laboratory Investigation

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Hepatic iron deposition unrelated to hereditary hemochromatosis occurs commonly in cirrhosis but the pathogenesis of this condition is unknown. The aim of this study was to compare the expression of genes involved in the regulation of iron metabolism in cirrhotic (n ¼ 22) and control human livers (n ¼ 5). Transcripts were quantitated by real-time RT-PCR and protein levels were assessed by western blot. Hepatic iron concentrations (HICs) were measured by a spectrophotometric method. Levels of hepcidin mRNA did not differ between controls and cirrhotic livers; there was a highly significant correlation between hepcidin transcript levels and HIC in the latter group. Ferroportin, divalent metal transporter-1 (DMT1), and ferritin heavy chain mRNA levels were significantly higher in cirrhotic human livers than in controls (P ¼ 0.007, 0.039, and 0.025, respectively). By western blot, ferroportin and DMT1 levels were generally diminished in the cirrhotic livers compared to controls; neither correlated with HIC. In contrast, the abundance of ferritin increased with increasing HIC in the cirrhotic livers, whereas transferrin receptor decreased, indicating physiologically appropriate regulation. In conclusion, hepcidin expression appears to be appropriately responsive to iron status in cirrhosis. However, there are complex alterations in DMT1 and ferroportin expression in cirrhotic liver, including decreases in ferroportin and DMT1 at the protein level that may play a role in aberrant regulation of iron metabolism in cirrhosis.

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Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function

Cited by 376 publications

References 32 publications

Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo

Acute study of interaction among cadmium, calcium, and zinc transport along the rat nephron in vivo

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

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