Discrepancy between the Nephrotoxic Potencies of Cadmium-Metallothionein and Cadmium Chloride and the Renal Concentration of Cadmium in the Proximal Convoluted Tubules

Dorian, C; Gattone, Vincent H.; Klaassen, Curtis D.

doi:10.1006/taap.1995.1021

Cited by 48 publications

(28 citation statements)

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“…In addition, cadmium-metallothionein-1, which is released from hepatic cells into the circulation, is small enough to be freely filtered by the glomerulus and then taken up by proximal tubule cells (Klaassen et al, 1999). Indeed, proximal tubule cells are affected by cadmium-metallothionein-1 but not by free Cd 2ϩ in vivo (Dorian et al, 1995;Sabolic et al, 2002). Hence, to gain greater insight into the mechanisms of Cd 2ϩ nephrotoxicity, the mechanisms of cadmium-metallothionein-1 uptake by a rat cell line derived from the S1 segment of kidney proximal tubule were investigated in more detail.…”

Section: Discussionmentioning

confidence: 99%

Megalin-Dependent Internalization of Cadmium-Metallothionein and Cytotoxicity in Cultured Renal Proximal Tubule Cells

Wolff¹,

Abouhamed²,

Verroust³

et al. 2006

J Pharmacol Exp Ther

119

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Chronic cadmium (Cd 2ϩ ) exposure results in renal proximal tubular cell damage. Delivery of Cd 2ϩ to the kidney occurs mainly as complexes with metallothionein-1 (molecular mass ϳ 7 kDa), freely filtered at the glomerulus. For Cd 2ϩ to gain access to the proximal tubule cells, these complexes are thought to be internalized via receptors for small protein ligands, such as megalin and cubilin, followed by release of Cd 2ϩ from metallothionein-1 in endosomal/lysosomal compartments. To investigate the role of megalin in renal cadmiummetallothionein-1 reabsorption, megalin expression and dependence of cadmium-metallothionein-1 internalization and cytotoxicity on megalin were studied in a renal proximal tubular cell model (WKPT-0293 Cl.2 cells). Expression of megalin was detected by reverse transcriptase-polymerase chain reaction and visualized by immunofluorescence both at the cell surface (live staining) and intracellularly (permeabilized cells). Internalization of Alexa Fluor 488-coupled metallothionein-1 was concentration-dependent, saturating at approximately 15 M. At 14.3 M, metallothionein-1 uptake could be significantly attenuated by 30.9 Ϯ 6.6% (n ϭ 4) by 1 M of the receptorassociated protein (RAP) used as a competitive inhibitor of cadmium-metallothionein-1 binding to megalin and cubilin. Consistently, cytotoxicity of a 24-h treatment with 7.14 M cadmium-metallothionein-1 was significantly reduced by 41.0 Ϯ 7.6%, 61.6 Ϯ 3.4%, and 26.2 Ϯ 1.8% (n ϭ 4 -5 each) by the presence of 1 M RAP, 400 g/ml anti-megalin antibody, or 5 M of the cubilin-specific ligand, apo-transferrin, respectively. Cubilin expression in proximal tubule cells was also confirmed at the mRNA and protein level. The data indicate that renal proximal tubular cadmium-metallothionein-1 uptake and cell death are mediated at least in part by megalin.

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Section: Discussionmentioning

confidence: 99%

Megalin-Dependent Internalization of Cadmium-Metallothionein and Cytotoxicity in Cultured Renal Proximal Tubule Cells

Wolff¹,

Abouhamed²,

Verroust³

et al. 2006

J Pharmacol Exp Ther

119

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“…Based on these results of the present study, it was thought that this Cd not bound to MT might be responsible for the toxic effects of Cd in the kidney. In other words, Cd cytotoxicity was thought to be dependent on the amount of non-CdMT present in renal cells, which is not sequestered by available endogenous MT or glutathione [69][70][71] . However, Dorian et al 71) also suggest that the nephrotoxic effect of CdMT is not due to a higher concentration of Cd in the target cells of the kidney being caused by CdMT than by CdCl 2 administration.…”

Section: Discussionmentioning

confidence: 99%

“…In other words, Cd cytotoxicity was thought to be dependent on the amount of non-CdMT present in renal cells, which is not sequestered by available endogenous MT or glutathione [69][70][71] . However, Dorian et al 71) also suggest that the nephrotoxic effect of CdMT is not due to a higher concentration of Cd in the target cells of the kidney being caused by CdMT than by CdCl 2 administration. In addition, it has been suggested that the tendency of CdMT to concentrate at the site where toxicity occurs (S1 and S2 segments of the proximal tubules) might explain why CdMT is nephrotoxic and CdCl 2 is not.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been suggested that the nephrotoxicity of CdMT is not merely due to renal Cd concentration 72) . Consequently, it is suggested that the two forms of Cd may be differ in their uptake paths into cells and their ability to cause injury inside cells 71) . Dorian et al have also reported that Cd administered as CdMT is distributed preferentially in the S1 and S2 segments of the proximal tubules, the site of Cd nephrotoxicity, but Cd from CdCl 2 is not 38) .…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that the cellular effects of Cd toxicity, which begin with formation of pinocytotic vesicles of the luminal surface followed by focal mitochondrial changes, can vary from slight swelling to frank necrosis and swelling 28,33,37,[71][72][73][74][75] . We examined the histopathological changes in renal tissue caused by Cd accumulation.…”

Section: Discussionmentioning

confidence: 99%

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Relationship between Renal Dysfunction and Bone Metabolism Disorder in Male Rats after Long-Term Oral Quantitative Cadmium Administration.

et al. 2000

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To investigate the importance of the cadmium (Cd) exposure condition in the evaluation of toxic effect on renal function and bone metabolism, six groups of Male Wistar rats were given Cd at respective daily doses of 2, 5, 10, 20, 30 and 60 mgCd/kg (as CdCl 2 ) via a gastric tube for 6 consecutive days a week for 60 weeks. In the groups given a low Cd dose (2, 5 and 10 mgCd/kg), relatively more Cd accumulated in the kidney without liver damage than in the liver. In the high Cd dose groups (20, 30 and 60 mgCd/kg), on the other hand, more Cd accumulated in the liver than in the kidney. The daily intake of Cd dose from the intestinal tract in each experimental group was deduced to be about 0.36%-0.54% of the cumulative dose of oral Cd administration. The daily intake of Cd into the body was estimated as 7, 22, 40, 100, 120, 260 µgCd/kg/day in the experimental groups of 2, 5, 10, 20, 30 and 60 mgCd/kg/day, respectively. Increase of plasma enzyme activity (GOT, GPT) and of urinary enzyme excretion (NAG, AAP, GST), reflecting hepatic damage and renal dysfunction, was found in the high Cd dose groups (30 and 60 mgCd/kg) from the 5th week. Non-CdMT concentration in the kidney was also significantly high in the high Cd dose groups. In the low Cd dose groups (2 and 5 mgCd/kg), although the renal Cd concentration was higher than that of the high Cd dose groups, prominent renal dysfunction and hepatic damage were not observed. Regeneration, vacuolization, and eosinophilic bodies in proximal tubular tissue were mainly observed in the groups subjected to 20, 30 and 60 mgCd/kg administration. Very slight regeneration was also observed in the renal proximal tubular tissue at the 30th week for the 5 mgCd/kg and 10 mgCd/kg groups, and at the 60th week for the 2 mgCd/kg group. Remarkable decrease of bone mineral density at the midpoint of the femur was found in the high Cd dose groups. Also, the decrease in bone mineral density was observed before or after the manifestation of the renal dysfunction, depending on the dose and the duration of Cd administration. Urinary excretion of Pyr, DPyr, and Ca increased and plasma BGP decreased in the higher Cd dose groups. Osteoid volume in the femur tissue was not increased significantly by Cd exposure. Based on these results, it was suggested that Cd exposure caused osteoporotic change. The results of the present study suggested that the toxic effect of Cd on renal function and that on bone metabolism were caused at different times and that renal Cd concentration after long-term oral Cd administration depended on the dose and the duration of Cd exposure.

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Selenium supplementation during cadmium exposure: Changes in antioxidant enzymes and the ultrastructure of the kidney

Jamba

Nehru

Bansal

1997

J. Trace Elem. Exp. Med.

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Cadmium exposure in mice (8 mg Cd as CdCl 2 /kg bw, for 8 weeks, daily oral) resulted in increased cadmium levels in kidney and liver. The level was quite high in kidney (3 times) as compared to liver. However when selenium (0.35 mg Se as Na 2 SeO 3 /kg bw, daily, orally for 8 weeks) was administered concurrently, a significant decrease in cadmium level was seen in kidney and liver.Cadmium exposure resulted in apparent pathological changes in the proximal convoluted tubules (PCT) in kidney at the electron microscopic level. The mitochondria seem to be most severely affected among the cellular organelles. The alterations included swelling and dilation of the organelles. The cristae showed a disorganized architecture. Activities of the antioxidant enzymes glutathione peroxidase (GSH-Px) and catalase in kidney were also significantly inhibited. However, when selenium was co-administered, the structural integrity of the PCT was comparable to the control. The activity of the antioxidant enzymes was also restored to normal levels.This study suggests that cadmium manifests toxic effects by disrupting the antioxidant enzyme system, which in turn affects the membranous structures such as mitochondria and endoplasmic reticulum. This, in turn, affects the oxidative phosphorylation. Further, it is observed that the co-administration of selenium diminishes the effects of cadmium.

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Discrepancy between the Nephrotoxic Potencies of Cadmium-Metallothionein and Cadmium Chloride and the Renal Concentration of Cadmium in the Proximal Convoluted Tubules

Cited by 48 publications

References 0 publications

Megalin-Dependent Internalization of Cadmium-Metallothionein and Cytotoxicity in Cultured Renal Proximal Tubule Cells

Megalin-Dependent Internalization of Cadmium-Metallothionein and Cytotoxicity in Cultured Renal Proximal Tubule Cells

Relationship between Renal Dysfunction and Bone Metabolism Disorder in Male Rats after Long-Term Oral Quantitative Cadmium Administration.

Selenium supplementation during cadmium exposure: Changes in antioxidant enzymes and the ultrastructure of the kidney

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