Renal Organic Anion Transport System: A Mechanism for the Basolateral Uptake of Mercury-Thiol Conjugates along the Pars Recta of the Proximal Tubule

Zalups, Rudolfs K.

doi:10.1006/taap.2002.9448

Cited by 40 publications

(18 citation statements)

References 26 publications

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“…preponderance of this accumulation occurring in proximal tubular epithelial cells (1,(22)(23)(24). At least one luminal mechanism and at least one basolateral mechanism have been shown to be responsible for the uptake of mercuric ions by proximal tubular epithelial cells (5)(6)(7)(8)(9)(10)(11)(12)(13)25,26).…”

Section: Discussionmentioning

confidence: 99%

“…It is interesting that current evidence indicates that there are indeed both luminal and basolateral mechanisms involved in the proximal tubular uptake and accumulation of Hg (1). Several lines of evidence have emerged indicating that mercuric conjugates of cysteine (Cys), in the form of 2-amino-3-(2-amino-2-carboxy-ethylsulfanylmercuricsulfanyl) propionic acid (Cys-S-Hg-S-Cys), are substrates that can be taken up from the blood and extracellular fluid by proximal tubular epithelial cells at their basolateral membrane by one or more organic anion transport systems (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The most conclusive evidence implicating the organic anion transporters has come recently from two studies that used type II MDCK cells transfected stably with the human isoform of oat1.…”

mentioning

confidence: 99%

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Homocysteine and the Renal Epithelial Transport and Toxicity of Inorganic Mercury

Zalups

Ahmad²

2004

Journal of the American Society of Nephrology

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Abstract. The epithelial cells that line the renal proximal tubule have been shown to be the primary cellular targets where mercuric ions gain entry, accumulate, and induce pathologic effects in vivo. Recent data have implicated at least one of the organic anion transport systems in the basolateral uptake of inorganic mercury (Hg). With the use of a line of type II MDCK cells transfected stably with the human organic anion transporter 1 (hOAT1), the hypothesis that hOAT1 can transport mercuric conjugates of homocysteine (Hcy) was tested. Indeed, MDCK II cells expressing a functional form of hOAT1 gained the ability to transport the mercuric conjugate 2-amino-4-(3-amino-3-carboxy-propylsulfanylmercuricsulfanyl) butyric acid (Hcy-S-Hg-S-Hcy). In addition, p-aminohippurate and the dicarboxylates adipate and glutarate (but not succinate or malonate) inhibited individually the uptake of Hcy-S-Hg-S-Hcy in a concentration-dependent manner. Furthermore, a direct relationship between the uptake of Hcy-S-Hg-S-Hcy and the induction of cellular injury and death was demonstrated in the hOAT1-expressing MDCK II cells only. These data represent the first line of direct evidence implicating one of the organic anion transporters in the uptake of a mercuric conjugate of Hcy in a mammalian cell. Thus, mercuric conjugates of Hcy are potential transportable substrates of OAT1. More important, the findings from the present study implicate the activity of OAT1 in the uptake and toxicity of Hg (when in the form of Hcy-S-Hg-SHcy in the extracellular compartment) in proximal tubular epithelial cells in vivo.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Homocysteine and the Renal Epithelial Transport and Toxicity of Inorganic Mercury

Zalups

Ahmad²

2004

Journal of the American Society of Nephrology

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“…Mercuric conjugates of glutathione are taken up in significant quantities at the basolateral membrane of the renal proximal tubule by an organic anion transport system [30]. Glutathione cis inhibits oatp1-mediated leukotriene C 4 and taurocholate uptake [31].…”

Section: Introductionmentioning

confidence: 99%

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Lu¹,

Tamai²,

Nezu³

et al. 2006

J Biomed Sci

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SummaryArsenic is an established human carcinogen. The role of aquaglyroporins (AQPs) in arsenic disposition was recently identified. In order to examine whether organic anion transporting polypeptide-C (OATP-C) also plays a role in arsenic transport, OATP-C cDNA was transfected into cells of a human embryonic kidney cell line (HEK-293). Transfection increased uptake of the model OATP-C substrate, estradiol-17b-D-glucuronide, by 10-fold. In addition, we measured uptake and cytotoxicity of arsenate, arsenite, monomethylarsonate(MMA V ), and dimethylarsinate (DMA V ). Transfection of OATP-C increased uptake and cytotoxicity of arsenate and arsenite, but not of MMA V or DMA V . Rifampin and taurocholic acid (a substrate of OATP-C) reversed the increased toxicity of arsenate and arsenite seen in OATP-C-transfected cells. The increase in uptake of inorganic arsenic was not as great as that of estradiol-17b-D-glucuronide. Our results suggest that OATP-C can transport inorganic arsenic in a (GSH)-dependent manner. However, this may not be the major pathway for arsenic transport.

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“…The thiol agent GSH readily complexes with divalent metals such as mercury, cadmium or zinc and uses the mammalian OAT1 transport protein to clear the blood of these metals by exchange with cytoplasmic AKG (e.g. GSH-Zn/AKG) or other cytoplasmic organic anions (Zalups and Barfuss, 2002). The results of the present investigation suggest that uptake of 65 …”

Section: Discussionmentioning

confidence: 66%

“…The OAT1 (organic anion transporter) is an organic anion exchanger that has been identified in mammals as a heavy metal transport system that transports thiol conjugates of metals (Zalups and Barfuss, 2002). In order to see whether an ortholog of the mammalian OAT1 transporter might be present in hepatopancreatic lysosomal membranes, and be responsible for the exchange of GSH-Zn 2+ /AKG as described by the sigmoidal influx of metal in Fig.…”

Section: Western Blot Analysis Of Possible Lysosomal Zinc Transportermentioning

confidence: 99%

Dual control of cytosolic metals by lysosomal transporters in lobster hepatopancreas

Sterling

Roggenbeck

Ahearn

2010

Journal of Experimental Biology

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SUMMARY This study describes the membrane transport mechanisms used by lobster (Homarus americanus) hepatopancreatic epithelial lysosomes to accumulate and sequester heavy metals from the cytosol, and thereby aid in the regulation of these ions entering the animal from dietary constituents. The present investigation extends previous work describing lysosomal metal uptake by cation exchange with protons and suggests that a second, parallel, lysosomal transport process involving metal—thiol conjugates may work in conjunction with the cation antiporter to control cytoplasmic metal concentrations. Transport of 65Zn2+ by lysosomal membrane vesicles (LMV) incubated in 1 mmol l−1 glutathione (GSH) was not significantly different from metal transport in the absence of the tripeptide. However, preloading LMV with 1 mmol l−1 α-ketoglutarate (AKG), and then incubating in a medium containing 1 mmol l−1 GSH, more than doubled metal uptake, compared with vesicles equilibrated with chloride or possessing an outwardly directed chloride gradient. Kinetic analysis of lysosomal 65Zn2+ influx as a function of zinc concentration, in vesicles containing 1 mmol l−1 AKG and incubated in 1 mmol l−1 GSH, revealed the presence of a sigmoidal, low affinity, high capacity carrier process transporting the metal into the organelle. These data indicated the possible presence of an organic anion exchanger in lobster lysosomal membranes. Western blot analysis of LMV with a rabbit anti-rat OAT1 antibody showed the presence of an orthologous OAT1-like protein (approximate molecular mass of 80 kDa) signal from these membranes. These results, and those published previously, suggest the occurrence of two metal transporters on hepatopancreatic membranes, a high affinity, low capacity cation antiporter and a low affinity, high capacity organic anion exchanger. Together these two systems have the potential to regulate cytoplasmic metals over a wide concentration range.

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Renal Organic Anion Transport System: A Mechanism for the Basolateral Uptake of Mercury-Thiol Conjugates along the Pars Recta of the Proximal Tubule

Cited by 40 publications

References 26 publications

Homocysteine and the Renal Epithelial Transport and Toxicity of Inorganic Mercury

Homocysteine and the Renal Epithelial Transport and Toxicity of Inorganic Mercury

Organic anion transporting polypeptide-C mediates arsenic uptake in HEK-293 cells

Dual control of cytosolic metals by lysosomal transporters in lobster hepatopancreas

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