Xenobiotic transporters and kidney injury

George, Blessy; You, Dahea; Joy, Melanie S.; Aleksunes, Lauren M.

doi:10.1016/j.addr.2017.01.005

Cited by 107 publications

(85 citation statements)

References 254 publications

(265 reference statements)

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“…These morphological alterations were a clear index of renal tubular injury. The proximal tubules showed the greater damage; it is not surprising because they are the major sites of accumulation of xenobiotics, as a result they fulfil the hard function to absorb and excrete the toxic substances.…”

Section: Discussionmentioning

confidence: 99%

Combined effects of DDE and hyperlipidic diet on metallothionein expression and synthesis in rat tissues

Migliaccio

Lionetti

Putti

et al. 2018

Environmental Toxicology

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Metallothionein is well known for its detoxificant and anti-oxidant properties and has been shown to be effective to prevent hydroxyl radical-generated DNA degradation. The purpose of this investigation was to analyze the combined effect of two factors promoting cellular oxidative-stress, that is, the administration of the pesticide dichloro-diphenyl-dichloroethylene (DDE) and a high fat diet, on metallothionein expression and synthesis in rat liver and kidney.DDE is the main metabolite of dichloro-diphenyl-trichloroethane (DDT), and is commonly found in the food chain and in all tissues of living organisms, carried by the fats. Male Wistar rats were fed with a standard (N) or a high fat (HF) diet and exposed to DDE (10 mg/kg body mass, N + DDE and HF + DDE groups) or vehicle (corn oil, N, and HF groups) via gavage every day for 28 days. Tissues histology was determined by light microscopy analysis; differences in metallothionein gene expression and synthesis by real-time PCR and western blot, respectively.Finally, protein cellular localization was established by immunocytochemistry. The results showed a different involvement of metallothionein in defending tissues from HF-and DDEinduced oxidative stress, suggesting that hepatic and renal cells use different strategies against pro-oxidant species. In both cell types a marked increase in the metallothionein content was observed in the nucleus, with a concomitant drop of the cytoplasmatic protein, either under HFand DDE-stress conditions; however, no synergistic or additive effects were observed between the action of fats and pesticide. These findings reinforce the role of metallothionein in protecting DNA from oxidative damage. K E Y W O R D SDDE and oxidative stress, gene expression, high fat diet, metallothionein, protein synthesis and localization

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Section: Discussionmentioning

confidence: 99%

Combined effects of DDE and hyperlipidic diet on metallothionein expression and synthesis in rat tissues

Migliaccio

Lionetti

Putti

et al. 2018

Environmental Toxicology

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“…Drug-induced nephrotoxicity is a major problem in clinical human therapy since the use of nephrotoxic drugs is often unavoidable. Thus, the prediction of drug nephrotoxicity appears of particular relevance in order to avoid kidney injury and/or perturbation of pharmacokinetic drug properties that are closely related to kidney excretion [14]. Moreover, the possibility to optimise drug design by using a functional screening in vitro model represents an interesting tool for the characterization of drug toxicity and/or for the development of news drugs.…”

Section: Discussionmentioning

confidence: 99%

Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations

Delézay

Hé

Hodin

et al. 2017

Experimental Cell Research

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The kidney is an organ that plays a major role in the excretion of numerous compounds such as drugs and chemicals. However, a great number of pharmacological molecules are nephrotoxic, affecting the efficiency of the treatment and increasing morbidity or mortality. Focusing on glomerular filtration, we propose in this study a simple and reproducible in vitro human model that is able to bring to light a functional podocyte injury, correlated with morphologic/phenotypic changes after drug exposure. This model was used for the evaluation of paracellular permeability of FITC-dextran molecules as well as FITC-BSA after different treatments. Puromycin aminonucleoside and adriamycin, compounds known to induce proteinuria in vivo and that serve here as positive nephrotoxic drug controls, were able to induce an important increase in fluorescent probe passage through the cell monolayer. Different molecules were then evaluated for their potential effect on podocyte filtration. Our results demonstrated that a drug effect could be time dependent, stable or scalable and relatively specific. Immunofluorescence studies indicated that these functional perturbations were due to cytoskeletal perturbations, monolayer disassembly or could be correlated with a decrease in nephrin expression and/or ZO-1 relocation. Taken together, our results demonstrated that this in vitro human model represents an interesting tool for the screening of the renal toxicity of drugs.

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“…Computational modeling suggests that As binds to free thiols on the MT molecule [79,80], which may reduce the oxidative injury induced by exposure to As [81]. Interestingly, it has been suggested that the formation of MT-As complexes does not occur following acute exposure to iAs; rather, it was postulated that these complexes are formed only in cases of chronic exposure [82].…”

Section: Environmentally Relevant Toxic Metalsmentioning

confidence: 99%

Chronic Kidney Disease and Exposure to Nephrotoxic Metals

Orr

Bridges

2017

IJMS

304

110

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Chronic kidney disease (CKD) is a common progressive disease that is typically characterized by the permanent loss of functional nephrons. As injured nephrons become sclerotic and die, the remaining healthy nephrons undergo numerous structural, molecular, and functional changes in an attempt to compensate for the loss of diseased nephrons. These compensatory changes enable the kidney to maintain fluid and solute homeostasis until approximately 75% of nephrons are lost. As CKD continues to progress, glomerular filtration rate decreases, and remaining nephrons are unable to effectively eliminate metabolic wastes and environmental toxicants from the body. This inability may enhance mortality and/or morbidity of an individual. Environmental toxicants of particular concern are arsenic, cadmium, lead, and mercury. Since these metals are present throughout the environment and exposure to one or more of these metals is unavoidable, it is important that the way in which these metals are handled by target organs in normal and disease states is understood completely.

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Xenobiotic transporters and kidney injury

Cited by 107 publications

References 254 publications

Combined effects of DDE and hyperlipidic diet on metallothionein expression and synthesis in rat tissues

Combined effects of DDE and hyperlipidic diet on metallothionein expression and synthesis in rat tissues

Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations

Chronic Kidney Disease and Exposure to Nephrotoxic Metals

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