Copper–metallothionein in the Kidney of Macular Mice: A Model for Menkes Disease

Suzuki-Kurasaki, Mika; Okabe, Masaru; Kurasaki, Masaaki

doi:10.1177/002215549704501106

Cited by 43 publications

(24 citation statements)

References 49 publications

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“…In contrast, in macular mice, which have impaired ATP7A, Cu-MT was seen only in the cells of proximal convoluted tubules (30,32). These early results point to an important involvement of both ATP7A and ATP7B in copper homeostasis in proximal tubules.…”

Section: Discussionmentioning

confidence: 84%

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b^−/−kidney

Linz¹,

Barnes²,

Zimnicka³

et al. 2008

American Journal of Physiology-Renal Physiology

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Kidneys regulate their copper content more effectively than many other organs in diseases of copper deficiency or excess. We demonstrate that two copper-transporting ATPases, ATP7A and ATP7B, contribute to this regulation. ATP7A is expressed, to a variable degree, throughout the kidney and shows age-dependent intracellular localization. In 2-wk-old mice, ATP7A is located in the vicinity of the basolateral membrane, whereas in 20-wk-old mice, ATP7A is predominantly in intracellular vesicles. Acute elevation of serum copper, via intraperitoneal injection, results in the in vivo redistribution of ATP7A from intracellular compartments toward the basolateral membrane, illustrating a role for ATP7A in renal response to changes in copper load. Renal copper homeostasis also requires functional ATP7B, which is coexpressed with ATP7A in renal cells of proximal and distal origin. The kidneys of Atp7b−/−mice, an animal model of Wilson disease, show metabolic alterations manifested by the appearance of highly fluorescent deposits; however, in marked contrast to the liver, renal copper is not significantly elevated. The lack of notable copper accumulation in the Atp7b−/−kidney is likely due to the compensatory export of copper by ATP7A. This interpretation is supported by the predominant localization of ATP7A at the basolateral membrane of Atp7b−/−cortical tubules. Our results suggest that both Cu-ATPases regulate renal copper, with ATP7A playing a major role in exporting copper via basolateral membranes and protecting renal tissue against copper overload.

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Section: Discussionmentioning

confidence: 84%

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b^−/−kidney

Linz¹,

Barnes²,

Zimnicka³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…Second, heavy metals such as Pt are known to induce leakage of lysosomes, causing release of hydrolytic enzymes into the cytosol and leading to eventual cell death. Previously Nordberg & Nordberg (1987) and our group (Okabe et al 1996;Suzuki-Kurasaki et al 1997;Kurasaki et al 1998) reported that heavy metal-binding metallothioneins were incorporated into lysosomes to degrade the protein causing the release of heavy metals from metallothionein, and that the released metals act as inducers for metallothionein synthesis. The repeated metallothionein synthesis might affect their toxicity in the kidney cells.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Metallothionein on DNA Damage in Rat Kidney Caused by Cis‐Diamminedichloroplatinum

Hosokawa

Okabe

Saito

et al. 2000

Pharmacology & Toxicology

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Cis-diamminedichloroplatinum (cis-DDP) has been used as an anticancer agent but it also causes nephrotoxicity. To study the cis-DDP metabolism and its effects, the induction of metallothioneins and DNA damage caused by cis-DDP were observed. Cis-DDP or trans-DDP was administered to seven-week-old Wistar male rats as three daily injections of 8.0 mg/kg body wt., intraperitoneally. Using the obtained kidneys, gel filtration assay, metal analysis, immunohistochemistry and terminal deoxy transferase-mediated deoxy uracil triphosphate nick end labeling (TUNEL) method were carried out to examine localization of metallothioneins and DNA damage caused by cis-DDP. Platinum (Pt) contents, 26.05∫12.01 mg/g body wt. and 51.29∫4.59 mg/g body wt. (average∫S.E.) were detected in the kidney of rats injected with both cis-and trans-DDP, respectively. Metallothionein was detected in the cortex of the kidney in rats administrated cis-DDP or trans-DDP. The mRNA was also detected in the same region. On the other hand cis-DDP showed induction of DNA damage on the cells in the outer stripe of the outer medulla but trans-DDP did not show any damage. The regioninduced DNA damage differed from that induced by metallothioneins. Cis-DDP is suggested to be mainly trapped at the proximal tubules by metallothioneins, and the rest of cis-DDP induces DNA damage at the outer stripe of the outer medulla. Metallothioneins are considered to contribute to the protection against cis-DDP in the rat cortex.

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“…Mutations of MT are associated with several copper-storage diseases (33,45). MT also carries the commonly prescribed therapeutics gold and cisplatinum: both of these are limited in acute dose selection and duration of chronic therapy by nephrotoxicity based in the renal proximal tubule (7,18,36,42,43).…”

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confidence: 99%

“…Understanding the process of heavy metal uptake is critical in both physiology and therapeutics because heavy metals have a narrow margin between their essential or useful and their toxic levels (45). Mutations of MT are associated with several copper-storage diseases (33,45).…”

mentioning

confidence: 99%

Megalin mediates renal uptake of heavy metal metallothionein complexes

Klassen

Crenshaw²,

Kozyraki³

et al. 2004

American Journal of Physiology-Renal Physiology

121

107

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Prompted by reports that MT-I interferes with renal uptake of the megalin ligand ␤2-microglobulin in conscious rats, we tested the hypothesis that megalin binds MT and mediates its uptake. Three lines of evidence suggest that binding of MT to megalin is critical in renal proximal tubular uptake of MT-bound heavy metals. First, MT binds megalin, but not cubilin, in direct surface plasmon resonance studies. Binding of MT occurs at a single site with a Kd ϳ10 Ϫ4 and, as with other megalin ligands, depends on divalent cations. Second, antisera and various known megalin ligands inhibit the uptake of fluorescently labeled MT in model cell systems. Anti-megalin antisera, but not control sera, displace Ͼ90% bound MT from rat renal brush-border membranes. Megalin ligands including ␤2-microglobulin and also recombinant MT fragments compete for uptake by megalin-expressing rat yolk sac BN-16 cells. Third, megalin and fluorescently labeled MT colocalize in BN-16 cells, as shown by fluorescent microscopic techniques. Follow-up surface plasmon resonance and flow cytometry studies using overlapping MT peptides and recombinant MT fragments identify the hinge SCKKSCC region of MT as a critical site for megalin binding. These findings suggest that disruption of the SCKKSCC motif can inhibit proximal tubular MT uptake and thereby eliminate much of the renal accumulation and toxicity of heavy metals such as cadmium, gold, copper, and cisplatinum. cadmium; cisplatin; cubilin; proximal tubules HEAVY METALS COMPLEXED TO metallothionein (MT) class I disturb many functions within the proximal tubules, but the entry route of these complexes into epithelial cells remains unknown (10,14,16,23,24,27,31,44). The best-studied heavy metal at present is cadmium. Environmental and occupational exposure to cadmium are widespread but mostly chronic and low level (1). Whether ingested or inhaled, the majority of absorbed cadmium eventually complexes with MT (9, 32), which is produced by several tissues and is largely intracellular but readily detectable at low levels in the circulation. The resulting heavy metal complex Cd-MT, containing seven cadmium ions (Fig. 1), is small enough (ϳ7 kDa) to be freely filtered through the renal glomerulus into the proximal tubular fluid, before reuptake into proximal tubular cells (15).Although neither the apoprotein nor the zinc complex appears toxic, Cd-MT is a renal tubular toxin whose damage is marked by proteinuria, glucosuria, and aminoaciduria, or in more severe cases, acute tubular necrosis or chronic renal failure (37). Conflicting reports implicate different transporters or, more likely, receptor-mediated pathways in the cellular uptake of Cd-MT (4,5,15,22,28,47). At least some of the uncertainty concerning uptake pathways arises from the use of in vivo and in vitro models that differ significantly in their behavior. For example, while CdCl 2 is more toxic than Cd-MT to cultured rat kidney proximal tubules and LLC-PK 1 cells, Cd-MT shows greater in vivo nephrotoxic effects (26,27,35). Furthermore, in vi...

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Copper–metallothionein in the Kidney of Macular Mice: A Model for Menkes Disease

Cited by 43 publications

References 49 publications

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b^−/−kidney

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b^−/−kidney

Protective Role of Metallothionein on DNA Damage in Rat Kidney Caused by Cis‐Diamminedichloroplatinum

Megalin mediates renal uptake of heavy metal metallothionein complexes

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Copper–metallothionein in the Kidney of Macular Mice: A Model for Menkes Disease

Cited by 43 publications

References 49 publications

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b−/−kidney

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b−/−kidney

Protective Role of Metallothionein on DNA Damage in Rat Kidney Caused by Cis‐Diamminedichloroplatinum

Megalin mediates renal uptake of heavy metal metallothionein complexes

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Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b^−/−kidney

Intracellular targeting of copper-transporting ATPase ATP7A in a normal andAtp7b^−/−kidney