Nephrotoxicity of uranyl acetate: effect on rat kidney brush border membrane vesicles

Goldman, Michael; Yaari, A; Doshnitzki, Z; Cohen‐Luria, Rivka; Moran, Arie

doi:10.1007/s00204-006-0064-6

Cited by 34 publications

(14 citation statements)

References 17 publications

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“…Ainsi une diminution de la consommation d'ATP a été observée sur des cellules rénales en cultures exposées à l'uranium. Par ailleurs, le transport du glucose ainsi que son métabolisme au sein du TCP serait également affecté après exposition à l'uranium et en ferait un 4 e transporteur altéré par l'uranium au niveau cellulaire (Goldman et al, 2006 ;Renault et al, 2010 ;Vicente-Vicente et al, 2010).…”

Section: Transporteurs D'électrolytes Et Solutésunclassified

Données nouvelles sur la néphrotoxicité de l’uranium

Guéguen

Rouas

2012

Radioprotection

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RÉSUMÉL'uranium est un radioélément ainsi qu'un métal lourd auquel l'homme peut être exposé du fait de sa présence dans l'environnement ou des activités humaines. Il exerce principalement une toxicité chimique au niveau du tubule contourné proximal du rein après exposition aiguë ou chronique. Après exposition à une forte dose d'uranium, la néphrite tubulaire aiguë est révélée par une protéinurie ainsi qu'une diminution du débit de filtration glomérulaire. Plus récemment, l'utilisation de marqueurs d'intégrité tissulaire telle que la béta 2-microglobuline ou des enzymes tissulaires a pu être corrélée aux altérations histopathologiques des tubules contournés proximaux. Lors d'exposition chronique à de faible niveau, l'utilisation de marqueurs plus spécifiques et plus sensibles s'avère nécessaire lorsque les lésions sont faibles. Des études expérimentales développées au laboratoire ont montré la pertinence de certains de ces biomarqueurs tel que Kim-1 pour détecter de faibles altérations rénales. L'uranium exerce sa cytotoxicité au niveau des cellules épithéliales des tubules contournés proximaux probablement du fait de son entrée dans la cellule où il s'accumule préférentiellement dans le noyau cellulaire, lorsqu'il n'est pas sous forme de précipités. Les mécanismes conduisant à la mort des cellules ne sont pas encore totalement élucidés mais le stress oxydant semble y jouer un rôle important. ABSTRACT New data on uranium nephrotoxicity.Uranium is an element and also a heavy metal to which humans can be exposed due to its natural presence or human activities. It has mainly a chemical toxicity on the proximal convoluted tubules of the kidney after acute or chronic exposure. At high dose exposure, acute tubular nephritis is observed, as indicated by proteinuria and a decreased glomerular filtration rate. More recently, the use of structural biomarkers such as beta 2-microglobuline or tubular enzymes has been correlated with histopathological injury of the proximal convoluted tubules. During chronic exposure at a low level, the use of some of these sensitive and specific biomarkers would be necessary, particularly when the injury is slight. Recent experimental studies in the laboratory have shown the relevance of such new biomarkers as Kim-1 to detect slight renal injury. Uranium exerts its toxicity on epithelial tubular cells in which it accumulates mainly in the nucleus when it is not precipitated. The mechanisms leading to cell death are not totally elucidated but oxidative stress seems to play an important role.

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Section: Transporteurs D'électrolytes Et Solutésunclassified

Données nouvelles sur la néphrotoxicité de l’uranium

Guéguen

Rouas

2012

Radioprotection

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“…It is possible that exposure to uranium, a nephrotoxicant, may be contributing to an excess of kidney disease among the Navajo [20-22]. The age-adjusted prevalence of end-stage renal disease (ESRD) among the Navajo people is more than three times that of the general U.S. population [23].…”

Section: Introductionmentioning

confidence: 99%

Development of risk maps to minimize uranium exposures in the Navajo Churchrock mining district

deLemos

Brugge²,

Cajero

et al. 2009

Environ Health

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BackgroundDecades of improper disposal of uranium-mining wastes on the Navajo Nation has resulted in adverse human and ecological health impacts as well as socio-cultural problems. As the Navajo people become increasingly aware of the contamination problems, there is a need to develop a risk-communication strategy to properly inform tribal members of the extent and severity of the health risks. To be most effective, this strategy needs to blend accepted risk-communication techniques with Navajo perspectives such that the strategy can be used at the community level to inform culturally- and toxicologically-relevant decisions about land and water use as well as mine-waste remediation.ObjectiveThe objective of this study was to develop GIS-based thematic maps as communication tools to clearly identify high risk exposure areas and offer alternatives to minimize public and ecological health impacts.MethodsThematic maps were produced that incorporated data derived from environmental sampling and public health surveys. The maps show the location and quality of unregulated water resources and identify regulated water sources that could be used as alternatives. In addition, the maps show the location of contaminated soil and sediment areas in which disturbance of surface deposits should be avoided. Preliminary feedback was collected from an informal Navajo working group to assess the clarity and efficacy of this proposed communication method.ResultsThe working group found the maps to be both clear and effective, and made suggestions for improvements, such as the addition of more map features. The working group predicted that once the maps are presented to the public, water hauling and soil use behaviors will change, and dialogue with chapter officials will be initiated to accelerate further risk reduction efforts.ImplicationsBecause risk communication is complicated by language barriers, lack of infrastructure, and historical mistrust of non-Navajo researchers, mapping provides an easily interpretable medium that can be objectively viewed by community members and decision makers to evaluate activities that affect toxicant exposures.

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“…The chemical nephrotoxicity of uranium is pH dependent (Goldman et al, 2006) and characterized by the development of transepithelial transport and permeability defects (Leggett, 1989;Tyrakowski, 1979), inhibition of the Na þ /K þ ATPase activity and mitochondrial injury (Brady et al, 1989), gene expression alteration (Taulan et al, 2004(Taulan et al, , 2006, and possibly oxidative DNA damage (Miller et al, 2002). Uranium-induced toxicity is also dependent upon its speciation (Carrière et al, 2004;Mirto et al, 1999a,b;Muller et al, 2006), and we recently demonstrated the existence of a strong correlation between its toxicity, the level of phosphate, and the expression and activity of the NaPi-IIas (Muller et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Uranium-induced tubular alterations are mainly observed at the level of the second and third segment of the proximal tubule and can develop with a uranium concentration as low as 0.01 mg/kg of kidney. These alterations increase in severity as either time or uranium concentration is increased (Lopez et al, 2000) and are suggested to result in part from transepithelial transport permeability defects (Goldman et al, 2006;Leggett, 1989;Tyrakowski, 1979), inhibition of the Na þ /K þ ATPase activity, and mitochondrial injury (Brady et al, 1989). At high concentrations, these alterations are followed by necrosis (Bulger, 1986;McDonald-Taylor et al, 1997) and/or apoptosis (Sano et al, 1998).…”

mentioning

confidence: 99%

Role of the sodium-dependent phosphate co-transporters and of the phosphate complexes of uranyl in the cytotoxicity of uranium in LLC-PK1 cells

Müller

Houpert

Cambar

et al. 2006

Toxicology and Applied Pharmacology

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Although uranium is a well-characterized nephrotoxic agent, very little is known at the cellular and molecular level about the mechanisms underlying the uptake and toxicity of this element in proximal tubule cells. The aim of this study was thus to characterize the species of uranium that are responsible for its cytotoxicity and define the mechanism which is involved in the uptake of the cytotoxic fraction of uranium using two cell lines derived from kidney proximal (LLC-PK(1)) and distal (MDCK) tubule as in vitro models. Treatment of LLC-PK(1) cells with colchicine, cytochalasin D, concanavalin A and PMA increased the sodium-dependent phosphate co-transport and the cytotoxicity of uranium. On the contrary, replacement of the extra-cellular sodium with N-methyl-D-glucamine highly reduced the transport of phosphate and the cytotoxic effect of uranium. Uranium cytotoxicity was also dependent upon the extra-cellular concentration of phosphate and decreased in a concentration-dependent manner by 0.1-10 mM phosphonoformic acid, a competitive inhibitor of phosphate uptake. Consistent with these observations, over-expression of the rat proximal tubule sodium-dependent phosphate co-transporter NaPi-IIa in stably transfected MDCK cells significantly increased the cytotoxicity of uranium, and computer modeling of uranium speciation showed that uranium cytotoxicity was directly dependent on the presence of the phosphate complexes of uranyl UO(2)(PO(4))(-) and UO(2)(HPO(4))(aq). Taken together, these data suggest that the cytotoxic fraction of uranium is a phosphate complex of uranyl whose uptake is mediated by a sodium-dependent phosphate co-transporter system.

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Nephrotoxicity of uranyl acetate: effect on rat kidney brush border membrane vesicles

Cited by 34 publications

References 17 publications

Données nouvelles sur la néphrotoxicité de l’uranium

Données nouvelles sur la néphrotoxicité de l’uranium

Development of risk maps to minimize uranium exposures in the Navajo Churchrock mining district

Role of the sodium-dependent phosphate co-transporters and of the phosphate complexes of uranyl in the cytotoxicity of uranium in LLC-PK1 cells

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