Short- and Long-Term Influences of Heavy Metals on Anionic Drug Efflux from Renal Proximal Tubule

Terlouw, Sylvie A.; Graeff, Claudia; Smeets, Pascal H. E.; Fricker, Gert; Rüssel, Frans G. M.; Masereeuw, Rosalinde; Miller, David S.

doi:10.1124/jpet.301.2.578

Cited by 46 publications

(51 citation statements)

References 34 publications

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“…Previous studies on FL-MTX transport in killifish renal tubules have shown high inhibitory potencies of Mrp2 substrates and inhibitors in this process (25,26), as well as enhanced FL-MTX transport in vesicles overexpressing Mrp2 (49), thus confirming that FL-MTX transport in this assay is indeed mediated through Mrp2. The PTHrP used in this study was sea bream (Sparus auratus) recombinant PTHrP (resbPTHrP) (13,14).…”

supporting

confidence: 66%

“…Analogous to the results presented here, we predict that other calciotropic hormones, such as calcitonin and calcitriol, may influence organic anion transport. As mentioned before, these hormones influence [Ca 2ϩ ] i and/or use [Ca 2ϩ ] i as a second messenger (23,39,57,58), and high medium calcium levels are known to reduce Mrp2-mediated transport (48,49). Euryhaline fish such as sea bream and killifish easily adapt to waters with different salinities and calcium contents.…”

Section: Discussionmentioning

confidence: 99%

“…1) ET-regulated, Mrp2-mediated FL-MTX transport in fish kidney (25,26,49) is influenced by the calciotropic hormones PTH, PTHrP, and STC. 2) Both PTH and PTHrP inhibit transport, and the inhibition by ET is additive to the inhibition by PTHrP.…”

Section: Discussionmentioning

confidence: 99%

“…The nephrotoxicants induce ET release from the tubules followed by autocrine activation of the ET B -receptor/ NO/PKC pathway. Calcium influx through L-type channels is a stimulus for ET release on the short term; in the long term, Mrp2 expression and, in parallel, transport, are increased (49), also signaled through ET/NO (35).…”

mentioning

confidence: 99%

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Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

Wever¹,

Masereeuw²,

Miller³

et al. 2007

American Journal of Physiology-Renal Physiology

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Wever KE, Masereeuw R, Miller DS, Hang XM, Flik G. Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport. Am J Physiol Renal Physiol 292: F38 -F46, 2007. First published August 15, 2006; doi:10.1152/ajprenal.00479.2005.-The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP, and PKC (Notenboom S, Miller DS, Smits P, Russel FGM, Masereeuw R. Am J Physiol Renal Physiol 282: F458 -F464, 2002; Notenboom S, Miller DS, Smits P, Russel FG, Masereeuw R. Am J Physiol Renal Physiol 287: F33-F38, 2004). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study, we studied the effect of the calciotropic hormones parathyroid hormone (PTH), PTH-related protein (PTHrP), and stanniocalcin (STC) to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2-mediated transport by 40% in killifish renal proximal tubules. When given in combination, an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration dependent and additive to the inhibition by ET. STC fully reverses PTHrPinhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay, we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in ϳ40% of the tubules and is associated with the brush-border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling. parathyroid hormone; parathyroid hormone-related protein; stanniocalcin; xenobiotic transport; fluorescein-methotrexate; Sparus auratus; gilthead sea bream; Fundulus heteroclitus; killifish THE KIDNEY OF VERTEBRATES plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion. Secretion of xenobiotics in proximal tubules is mediated by carrier proteins, including members of the ATP-binding cassette (ABC) superfamily of transmembrane proteins (53). The multidrug resistance-associated protein 2 (Mrp2; ABCC2) belongs to this family. This transporter is found in liver canalicular membranes (6, 37), luminal membranes of the intestine (52), and luminal membranes of renal proximal tubule cells (42). Mrp2 transports a plethora of chemicals, from large lipophilic, organic ani...

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supporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

Wever¹,

Masereeuw²,

Miller³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…Controversially, cadmium salt (CdCl 2 ) was found not to be an inducer for Abcc2 expression in primary rat hepatocytes (Vernhet et al, 2001), but it was demonstrated to induce Abcc2 expression in isolated killifish renal proximal tubules (Terlouw et al, 2002). In this study, exposure to mercury and lead significantly induced the expression of zebrafish abcc2 gene; however, as analyzed with WISH, cadmium and arsenate displayed no induction effects on the expression of abcc2 in zebrafish larvae.…”

Section: Discussionmentioning

confidence: 52%

Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals

Long

Zhong

et al. 2011

Comparative Biochemistry and Physiology Part C: Toxicology &

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Renal Transport of Organic Anions and Cations

Pelis

Wright

2011

Comprehensive Physiology

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Organic anions and cations (OAs and OCs, respectively) comprise an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. The kidney, primarily the renal proximal tubule, plays a critical role in regulating the plasma concentrations of these organic electrolytes and in clearing the body of potentially toxic xenobiotics agents, a process that involves active, transepithelial secretion. This transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. Basolateral and luminal OA and OC transport reflects the concerted activity of a suite of separate proteins arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney, now allows the development of models describing the molecular basis of the renal secretion of OAs and OCs. New information on naturally occurring genetic variation of many of these processes provides insight into the basis of observed variability of drug efficacy and unwanted drug-drug interactions in human populations. The present review examines recent work on these issues.

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Short- and Long-Term Influences of Heavy Metals on Anionic Drug Efflux from Renal Proximal Tubule

Cited by 46 publications

References 34 publications

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

Molecular characterization and functions of zebrafish ABCC2 in cellular efflux of heavy metals

Renal Transport of Organic Anions and Cations

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