Multidrug and toxin extrusion proteins mediate cellular transport of cadmium

Yang, Hong; Guo, Dong; Obianom, Obinna N.; Su, Tian; Polli, James E.; Shu, Yan

doi:10.1016/j.taap.2016.11.007

Cited by 20 publications

(16 citation statements)

References 39 publications

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“…Our recent findings and those from others have indicated that OCT2 and MATEs are Cd ion transporters. [20][21][22] However, given their moderate affinity toward Cd ions, they are probably not the primary transport mechanisms for Cd. Other mechanisms or transporters, such as the receptor-mediated endocytosis of the Cd 2þ -protein complex, calcium channels, zinc transporters, transient receptor potential channels, divalent metal-ion transporters, amino acid/cystine transporters, and the adenosine triphosphatase multidrug resistance protein 1 (MDR1), have been implicated in transporting Cd across the membrane.…”

Section: Discussionmentioning

confidence: 99%

“…Cd has been reported to be a moderate substrate of OCTs 20,21 and MATEs. 22 Our initial intention was to examine the potential of Cd to inhibit OCT/MATE-mediated drug disposition. With stable human embryonic kidney (HEK)293 cells expressing human OCT2 (HEK-human(h)OCT2), we unexpectedly found that Cd pretreatment could increase the activities of human (h) OCT2 in a time-and concentrationdependent manner (Figure 1a; Supplementary Figure S1A).…”

Section: Exposure Increased Oct2 Activity and Its Membrane Expressionmentioning

confidence: 99%

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Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Yang

Tang

Guo

et al. 2020

Kidney International

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Renal accumulation and exposure of cadmium originating from pollution in agricultural land and the prevalence of cigarette smoking remains an unneglectable human health concern. Whereas cadmium exposure has been correlated with increased incidence of a variety of kidney diseases, little is known pertaining to its effect on renal drug disposition and response in patients. Here, we report that cadmium exposure significantly increased the activity of organic cation transporter 2 (OCT2), a critical renal drug transporter recommended in United States Federal Drug Administration guidance for assessment during drug development. Cadmium enhanced OCT2 trafficking to the cell membrane both in vitro and in vivo. Mechanistically cadmium-mediated OCT2 translocation was found to involve protein-protein interaction between serine/ threonine-protein kinase AKT2, calcium/calmodulin and the AKT substrate AS160 in in vitro cellular studies. The formed protein complex could selectively facilitate phosphorylation of AKT2 at T309, which induced translocation of OCT2 to the plasma membrane. Moreover, cadmium exposure markedly exacerbated nephrotoxicity induced by cisplatin, an OCT2 substrate, by increasing its accumulation in the mouse kidney. Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.

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Section: Discussionmentioning

confidence: 99%

Section: Exposure Increased Oct2 Activity and Its Membrane Expressionmentioning

confidence: 99%

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Yang

Tang

Guo

et al. 2020

Kidney International

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“…In Arabidopsis, the MATE-related transporter DETOXIFICATION 1 (AtDTX1) has been described as an efflux transporter that detoxifies plant-derived or exogenous toxic compounds including Cd from the cytoplasm [ 63 ]. Interestingly, a recent study on mammalian MATEs has provided the first evidence that MATE transporters are involved in the cellular transport and detoxification of Cd [ 64 ]. Therefore, it would be worth investigating the role of the Cd-induced plant MATE transporters in combating Cd toxicity in planta .…”

Section: Discussionmentioning

confidence: 99%

Co-expression network analysis of the transcriptomes of rice roots exposed to various cadmium stresses reveals universal cadmium-responsive genes

et al. 2017

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BackgroundThe migration of cadmium (Cd) from contaminated soil to rice is a cause for concern. However, the molecular mechanism underlying the response of rice roots to various Cd stresses remains to be clarified from the viewpoint of the co-expression network at a system-wide scale.ResultsWe employed a comparative RNAseq-based approach to identify early Cd-responsive differentially expressed genes (DEGs) in rice ‘Nipponbare’ seedling roots after 1 h of high-Cd treatment. A multiplicity of the identified 1772 DEGs were implicated in hormone signaling and transcriptional regulation, particularly NACs and WRKYs were all upregulated under Cd stress. All of the 6 Cd-upregulated ABC transporters were pleiotropic drug resistance proteins (PDRs), whereas all of the 6 ZRT/IRT-like proteins (ZIPs) were consistently downregulated by Cd treatment.To further confirm our results of this early transcriptomic response to Cd exposure, we then conducted weighted gene co-expression network analysis (WGCNA) to re-analyze our RNAseq data in combination with other 11 previously published RNAseq datasets for rice roots exposed to diverse concentrations of Cd for extended treatment periods. This integrative approach identified 271 transcripts as universal Cd-regulated DEGs that are key components of the Cd treatment coupled co-expression module. A global view of the 164 transcripts with annotated functions in pathway networks revealed several Cd-upregulated key functional genes, including transporter ABCG36/OsPDR9, 12-oxo-phytodienoic acid reductases (OPRs) for JA synthesis, and ZIM domain proteins JAZs in JA signaling, as well as OsWRKY10, NAC, and ZFP transcription factors. More importantly, 104 of these, including ABCG36/OsPDR9, OsNAC3, as well as several orthologs in group metalloendoproteinase, plastocyanin-like domain containing proteins and pectin methylesterase inhibitor, may respond specifically to various Cd pressures, after subtracting the 60 general stress-responsive genes reported to be commonly upregulated following multiple stresses.ConclusionAn integrative approach was implemented to identify DEGs and co-expression network modules in response to various Cd pressures, and 104 of the 164 annotatable universal Cd-responsive DEGs may specifically respond to various Cd pressures. These results provide insight into the universal molecular mechanisms beneath the Cd response in rice roots, and suggest many promising targets for improving the rice acclimation process against Cd toxicity.Electronic supplementary materialThe online version of this article (10.1186/s12870-017-1143-y) contains supplementary material, which is available to authorized users.

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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

288

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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Multidrug and toxin extrusion proteins mediate cellular transport of cadmium

Cited by 20 publications

References 39 publications

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Co-expression network analysis of the transcriptomes of rice roots exposed to various cadmium stresses reveals universal cadmium-responsive genes

Chronic Kidney Disease and Exposure to Nephrotoxic Metals

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