Renal Iron Metabolism: Transferrin Iron Delivery and the Role of Iron Regulatory Proteins
Deliang Zhang,
Esther Meyron-Holtz and
Tracey A. Rouault
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, Maryland
Address correspondence to: Dr. Tracey Rouault, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892. Phone: 301-496-7060; Fax: 301-402-0078; E-mail: trou{at}helix.nih.gov
In mammalian cells, iron is required for the function of manyprosthetic groups, including heme and iron-sulfur clusters.Mammals absorb dietary iron and heme across the apical mucosaof duodenal epithelial cells using a Fe2+ transporter knownas divalent metal transporter 1 (DMT-1; also known as solutecarrier family 11 member 2, divalent cation transporter 1 (DCT1),and natural resistance associated macrophage protein 2) (1)or a specific heme transporter, heme carrier protein 1 (2).On the basolateral membrane, ferroportin (also known as mentaltransport protein 1 and iron regulated transporter 1) exportsiron to the plasma (3), aided by hephaestin (4), which oxidizesferrous (Fe2+) to ferric (Fe3+) iron. Serum transferrin (Tf),a 78-kD glycoprotein that is secreted mainly by the liver, bindsone or two Fe3+ atoms. Each Fe3+ binds to four amino acid ligandsfrom Tf and additionally binds a carbonate anion that stabilizesiron binding by providing two oxygen ligands. Carbonate bindingcompletes occupancy of the six coordination positions of Fe3+and thereby stabilizes binding of Fe3+ to Tf. Tf-bound ironcirculates freely in the serum and extravascular spaces, andit serves as a source of iron for cells and tissues that areperfused by the systemic circulation, including liver, heart,muscle, kidney, and bone marrow (5). Excess intracellular ironis stored in ferritin, a heteropolymeric molecule that has aspherical shell structure and is composed of 24 H and L subunits,which can store up to 4500 iron atoms as a mineral core insidethe shell (6). Iron can be released from ferritin when cellsneed more iron either when ferritin is degraded in the lysosome(7) or through a pore in the ferritin shell (8).
Most cells modulate iron uptake by regulating the amount ofTf receptor 1 (TfR1) (9) that they express on the plasma membrane.The TfR functions as a dimer, and each 90-kD monomer has a singletransmembrane-spanning domain. Upon binding iron-bearing Tf,the TfR-Tf complex is internalized into an early endosome, whereacidification facilitates release of Fe3+ from Tf and a reductasereduces Fe3+ to Fe2+ (10), which then can be exported into cytosolby DMT-1 in the late endosomal/lysosomal compartment. A secondTfR that is expressed mainly by hepatocytes, TfR2, is not regulatedby intracellular iron levels and is unlikely to be importantin renal iron metabolism (11).
Renal Filtration of Tf and Proximal Tubule Resorption
In normal urine, the quantity of Tf is approximately 0.32 to0.47 mg/24 h (12), but in Fanconi syndrome, a disease that ischaracterized by generalized dysfunction of renal proximal tubules,urinary concentrations of Tf increase markedly (13). These findingsundermine the commonly held belief that the high molecular weightof Tf prevents it from being filtered by the glomerulus (14).In the proximal tubule, the cubilin receptor, which is highlyexpressed on the apical membrane of kidney proximal tubules,is thought to mediate uptake of Tf (15). Although DMT-1 hasbeen reported to localize to the apical membrane of proximaltubule cells (16), more recent studies suggest that DMT-1 localizeson the late endosomal and lysosomal membranes of proximal tubulecells, where it would facilitate the uptake of Tf-bound iron(17–19). In addition, when Tf is added to either the apicalor the basolateral membrane of a polarized cell line that isderived from proximal tubule cells, WKPT-0293 Cl.2 cells, Tfis internalized from the apical membrane but not from the basolateralmembrane (19). These findings also suggest that some Tf normallyenters glomerular filtrate, but it is retrieved by specificreceptor-mediated uptake in the kidney tubular system. It isinteresting that TfR is expressed on the apical membrane ofproximal tubule and collecting duct cells in mice (Figure 1),in distal convoluted tubules in the medulla of rats (20), andin all tubules in humans (21), offering a straightforward mechanismby which Tf can be retrieved from filtrate (Figure 2). It hasbeen found that Tf is an essential growth factor in the developmentof kidney and differentiation of tubule (22), and retrievalof Tf from filtrate may be the major mechanism by which proximaltubule cells acquire the iron that they need (19).
Figure 1. Localization of transferrin receptor (TfR) in mouse kidney. TfR expression was detected by immunofluorescence in the cortex (a) and medulla (b) of wild-type (WT) mouse kidney. TfR was highly expressed in the proximal tubule in kidney cortex, especially on the apical membrane of Bowman’s capsule (arrow) and proximal tubule (arrowhead), and also was expressed highly on the apical membrane of collecting tubule in medulla (M). There was no staining when primary antibody was omitted (c). Glomeruli in a and c are indicated (G). Paraffin-embedded tissue sections were boiled in a micro oven for 15 min for antigen retrieval after dewaxing and rehydrating. The sections were blocked in 5% normal goat serum in Tris-buffered saline with 0.1% Tween-20, then were incubated with (a and b) or without (c) monoclonal anti-TfR antibody (ZYMED Laboratories, South San Francisco, CA) for 2 h at room temperature, the protein–antibody complex was labeled by CY3-donkey anti-mouse antibody (red), nuclei were labeled by DAPI (blue), and the green color was generated by autofluorescence.
Figure 2. Localization of TfR and divalent metal transporter (DMT-1) in mouse kidney. TfR is localized on the apical membrane of proximal tubule and distal tubule, where it can bind diferric Tf in the glomerular filtrate. The Tf-TfR complex then is internalized into endosomes, whereupon the pH is lowered to approximately 5.5 to facilitate the release of iron from Tf. With the aid of a ferrireductase, the released iron can be exported into cytosol by DMT-1 that is localized at the endosomal/lysosomal membrane in proximal tubule. DMT-1 also is localized on the apical membrane of distal tubule, where it can resorb iron from tubular fluid. Illustration by Josh Gramling—Gramling Medical Illustration.
In the kidney-derived cell line MDCK, TfR localizes to the basolateralmembrane (23). It is not known which of the many cell typesin kidney gave rise to MDCK cells, and although the localizationof TfR in MDCK cells has been studied extensively, its physiologicrole in renal iron metabolism is not clear.
Renal Regulation of Ferritin and TfR Expression: Role of Iron-Responsive Elements and Iron Regulatory Proteins 1 and 2
In general, most cells regulate expression of ferritin, an ironsequestration protein, and TfR to meet their nutritional needs.Iron-regulatory proteins 1 and 2 (IRP1 and IRP2) regulate theexpression of both the H and L chains of ferritin, TfR1, andmultiple other iron proteins. IRP are cytosolic proteins thatsense cytosolic iron levels and bind to RNA stem-loop motifsthat are found in the mRNA transcripts of iron metabolism genes.These RNA motifs, known as iron-responsive elements (IRE), consistof conserved sequence and structural elements (Figure 3) (24,25).IRE consist of lower and upper base-paired stems, with an unpairedcytosine separating the upper and lower stems. A six-residueloop, usually with the sequence CAGUGX, where X can be any residuebut G, contains a base pair between C1 and G5 of the loop andresidues A2, G3, and U4 of the loop are free to move in solutionand form contacts with IRP. The IRE structure functions as amolecular ruler that positions two distinct RNA points of contactwith IRP: The bulge C that separates the upper and lower stemsand the A2, G3, and U4 residues of the loop (26). IRP regulatethe expression of IRE-containing transcripts by binding withhigh affinity to the IRE. When IRP bind to transcripts thatcontain an IRE in the 5' untranslated region (UTR), they repressits translation, whereas when they bind to the IRE in the 3'UTR of TfR1, they protect the transcript from endonucleolyticcleavage and increase TfR mRNA abundance (reviewed in references[27,28]).
Figure 3. Iron-responsive element (IRE) sequence and secondary structure. (a) The IRE contains a six-residue loop, usually with the sequence CAGYGX, where Y represents U or C and X represents any residue except G. The upper and lower stems are composed of base pairs of variable sequence (N-N') that are separated by an unpaired C. (b) In the nuclear magnetic resonance solution structure of a consensus IRE, a base pair forms between C1 and G5, and A2 stacks on G5 in the conserved loop sequence CAGUGX. The helical upper and lower stems have an A-form conformation, and both the bulge C and the unpaired G residue at position 3 in the loop are disordered in solution. The 5-bp upper stem most likely functions as a molecular ruler that orients and correctly distances the bulge C from residues in the loop, allowing flexible residues to participate in sequence-specific interactions between the IRE and iron-regulatory proteins (IRP). Adapted from reference (11), with permission, courtesy of K. Addess.
IRP1 and IRP2 share high sequence similarity and exhibit verysimilar biochemical activities with respect to their IRE-bindingaffinity, but their iron-sensing mechanisms are significantlydifferent. IRP1 is a bifunctional protein in which its activityis determined by the presence or absence of an iron-sulfur cluster(Figure 4). When IRP1 contains an iron-sulfur cluster in theactive site cleft, it functions as a cytosolic aconitase thatinterconverts citrate and isocitrate in cytosol (29). When theiron-sulfur cluster is absent, the fourth domain of IRP1 pivotson a flexible hinge linker to open a new binding space thatcan accommodate the IRE. Disassembly of the iron-sulfur clusteras a result of oxidation by superoxide (30), nitric oxide (31),and other oxidants increases the amount of IRP1 in the IRE-bindingform, whereas enzymes that are important in iron-sulfur clusterassembly promote the formation of the cytosolic aconitase formof the protein when there is sufficient iron to support iron-sulfurcluster synthesis (Figure 4) (29). When IRP1 is in the cytosolicaconitase form, it does not bind to IRE of the target transcripts,and the translation of H- and L-ferritin proceeds freely, creatinga 24-subunit spherical protein that can oxidize and sequesterseveral thousand Fe3+ atoms within its core (Figure 4). TfR1contains five IRE in its 3' UTR, and when IRP are not boundto the 3' UTR, TfR mRNA undergoes iron-dependent degradationand TfR levels decrease accordingly (32).
Figure 4. The iron-sulfur switch of IRP1. IRP1 is a bifunctional protein that can exist as a functional cytosolic aconitase when it binds an iron-sulfur cluster, interconverting citrate and isocitrate, or as an apoprotein that can bind IRE to regulate the expression of iron genes. The active site cleft that is responsible for aconitase activity overlaps with the region that binds to IRE, and binding of the iron-sulfur cluster prevents the binding with IRE. Thus, the unstable iron-sulfur prosthetic group may be the key determinant that switches IRP1 from an aconitase to the IRE-binding apoprotein, and numerous factors that can affect the formation or the disassembly of iron-sulfur cluster will regulate the IRP1 function and the expression of iron genes. For example, in iron-replete conditions, IRP1 will have an iron-sulfur cluster and will not bind IRE, and its inhibitory effect on ferritin translation will be absent, resulting in more ferritin synthesis (28).
IRP2 also binds to IRE in iron-depleted cells. However, unlikeIRP1, IRP2 undergoes iron-dependent ubiquitination and proteasomaldegradation in iron-replete cells (reviewed in references [27,28]).IRP2 is expressed ubiquitously throughout the mouse tissues,including kidney (Figure 5) (33). Animal studies have revealedthat IRP2 has a very significant role in regulation of tissueiron metabolism, and complete loss of IRP2 results in microcyticanemia, elevated serum ferritin, and late-onset neurodegeneration(34–36). The anemia results from decreased TfR expressionin erythroid precursor cells (34). Interstitial fibroblastsin the kidney respond to hypoxia that results from decreasedred cell oxygen-carrying capacity by secreting erythropoietin(37,38), and erythropoietin levels increase three- to five-foldin animals that lack IRP2, as expected in response to anemia(34).
Figure 5. Western blot analysis of the expression of IRP and L-ferritin in mouse kidney. The expression of IRP1 protein was unchanged in IRP2–/– mice compared with WT mice and was completely absent in IRP1–/– mice, as expected. The expression of IRP2 significantly increased in IRP1–/– mice compared with WT mice (P < 0.05), and there was no expression in IRP2–/– mice. L-ferritin expression was significantly increased in IRP knockout mice compared with WT mice (P < 0.01 for both genotypes), and the expression in IRP2–/– mice was higher than that in IRP1–/– mice (P < 0.01). Protein samples (60 µg for each lane) were separated in 4 to 20% SDS-acrylamide gel. The samples for each group were from three different mice. -Tubulin was used as loading control. The density of the bands was measured with ImageJ, and the data were analyzed with Microcal Origin 6.0.
Increased erythropoietin secretion by renal fibroblasts resultsfrom activation of hypoxia-inducible factors 1 and 2 (HIF-1and HIF-2) (39). When oxygen levels are normal, HIF undergohydroxylation by prolyl hydroxylases. Hydroxylated HIF thenare ubiquitinated by the Von Hippel-Lindau (VHL) complex andtargeted for degradation by the proteasome (40). Prolyl hydroxylasesdepend on Fe2+ for activity, and HIF levels therefore may increasein iron-deficient cells (41). It is interesting that the promotersof both TfR1 (42) (43) and Tf (44) contain HIF response elements,and mRNA levels of both TfR1 and Tf increase in iron-deficientcells.
Kidney is the mouse tissue in which IRP1 is most highly expressed(33). Animals that lack IRP1 are unable to repress ferritinsynthesis fully in the kidney under conditions of iron deficiency(33), demonstrating that IRP1 contributes significantly to regulationof iron metabolism in the kidney (Figures 5 and 6). In mostother tissues, loss of IRP1-binding activity does not lead tomisregulation of iron metabolism, because IRP2 levels increasein compensation (33,45). However, in kidney of IRP1–/–mice, although IRP2 levels increase in a compensatory manner,as expected, the increase in IRP2 is not sufficient to repressferritin synthesis completely (Figures 5 and 6). Failure torepress ferritin synthesis appropriately exacerbates iron deficiency,because ferritin competes effectively for available iron intissue culture cells (46) and in the kidney of intact animals(47). The ability of ferritin overexpression to create relativeiron deficiency likely is a major reason that ferritin expressionis tightly regulated. As for TfR, there is only a slight decreasein IRP1–/– or IRP2–/– mice comparedwith wild-type mice (D.Z., unpublished observations). TfR changesmay be difficult to assess in kidney lysates because differentcell types are mixed together in lysates. TfR mRNA degradationalso requires a specific but uncharacterized endonuclease thatmay be nonabundant in kidney (32) (Figures 1 and 5).
Figure 6. Ferritin expression in mouse kidney. Immunofluorescence showed ferritin expression in the kidney cortex of WT (a), IRP2–/– (b), and IRP1–/– (c) mice. Ferritin was expressed in the proximal tubule of mouse kidney. The expression of ferritin protein was increased in both IRP1–/– and IRP2–/– mice, and the upregulation in IRP2–/– mice was higher than that in IRP1–/– mice. Glomerulus was indicated by G. Paraffin-embedded tissue sections were probed with rabbit anti-ferritin antibody for 2 h at room temperature, then the protein–antibody complex was labeled by CY3-donkey anti-rabbit antibody (red) and nuclei were labeled by DAPI as counterstaining (blue).
IRP1 is highly expressed in proximal tubules of the kidney (Figure 7).The vast majority of IRP1 is an active aconitase at physiologicoxygen concentrations (33), and the high expression levels ofIRP1 in the proximal tubule may be explained by a need for cytosolicaconitase activity at this location. Proximal tubule cells reabsorb75 to 90% of the citrate that enters the glomerular filtrate(48), and this resorbed citrate likely is metabolized by cytosolicaconitase to yield isocitrate, which in turn can be metabolizedby cytosolic isocitrate dehydrogenase to yield 2-oxoglutarate,a carbon source that can replenish the mitochondrial citricacid cycle. Alternatively, 2-oxoglutarate could be transaminatedto produce glutamate, which could donate an amino group forurea formation. Kidneys filter and also likely secrete urea,and proximal tubule cells contain the argininosuccinate synthetaseand lyase enzymes of the urea cycle (49), raising the theoreticalpossibility that proximal renal tubular cells can secrete urea.Glutamate turnover is high in the proximal tubule (50). Thestriking localization of cytosolic aconitase to proximal tubulecells (Figure 7), together with the fact that most citrate inglomerular filtrate is resorbed at this site, suggests thatmuch of the resorbed citrate must be metabolized to isocitratefor further utilization.
Figure 7. Localization of IRP1 in mouse kidney. In situ hybridization showed the IRP1 mRNA expression in sections of WT mouse kidney at various magnifications: x20 (a), x10 (b), and x4 (c) (33). IRP1 mRNA was expressed in the proximal tubule of the kidney cortex (C) of WT mice, whereas there was little, if any, IRP1 mRNA in the kidney medulla (M). Immunofluorescence showed the IRP1 protein expression in mouse kidney (from WT mice [d and e] and from IRP1–/– mice [f]). IRP1 was highly expressed in the proximal tubule in kidney cortex (C), and there was very little expression in kidney medulla (M) and no label in the kidney of IRP1–/– mice. Glomeruli are indicated by G. Paraffin-embedded tissue sections were incubated with rabbit anti-IRP1 antibody for 2 h at room temperature, and the protein–antibody complex then was labeled by CY3-donkey anti-rabbit antibody (red); nuclei were labeled with DAPI (blue) for counterstaining.
In renal cancers in which the oncosuppressor VHL is inactivated,TfR levels increase markedly, perhaps because HIF levels increaseTfR transcription (51). Other aspects of iron metabolism havenot yet been described in detail in kidney cancers. Notably,iron can function as a renal carcinogen. Exposure of rats tohigh doses of ferric nitriloacetate predisposes to developmentof kidney cancer (52), but the mechanism by which iron inducescancer formation is not known.
IRP1 and IRP2 both regulate target transcripts, including ferritinand TfR posttranscriptionally in kidney. Specialized interstitialfibroblasts within the kidney are responsible for sensing hypoxiaand releasing erythropoietin. Hypoxia sensing depends on iron-dependentprolyl hydroxylases, which hydroxylate HIF and target HIF forubiquitination by VHL and proteasomal degradation. This pathwaymay regulate Tf and TfR transcription. It is likely that expressionof TfR on the apical membrane of proximal tubular cells hasan important role in retrieving Tf from glomerular filtrate.IRP1, which is expressed in extremely high levels in the kidney,is a bifunctional protein that has an important role as a cytosolicaconitase that converts citrate into isocitrate in proximaltubular cells. Proximal tubular cells resorb citrate, and cytosolicaconitase likely is needed to metabolize citrate. The ultimatefate of resorbed citrate in proximal tubular cells is not known.
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Introduction
Renal Filtration of Tf...
and 2
