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1 Department of Pharmacology and Toxicology, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands; 2 Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina 27709; and 3 Mount Desert Island Biological Laboratory, Salisbury Cove, Maine 04672
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We previously demonstrated in intact killifish renal proximal tubules that endothelin (ET), acting through an ETB receptor and protein kinase C (PKC), reduced transport mediated by multidrug resistance-associated protein 2 (Mrp2), i.e., luminal accumulation of fluorescein methotrexate (FL-MTX) (Masereeuw R, Terlouw SA, Van Aubel RAMH, Russel FGM, and Miller DS. Mol Pharmacol 57: 59-67, 2000). In the present study, we used confocal microscopy and quantitative image analysis to measure Mrp2-mediated transport of FL-MTX in killifish tubules as an indicator of the status of this ET-fired, intracellular signaling pathway. Exposing tubules to sodium nitroprusside (SNP), a nitric oxide (NO) donor, signaled a reduction in luminal accumulation of FL-MTX, which suggested pathway activation. NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, blocked the action of ET-1 on transport. Because SNP effects on transport were blocked by bisindoylmaleide, a PKC-selective inhibitor, but not by RES-701-1, an ETB-receptor antagonist, generation of NO occurred after ETB receptor signaling but before PKC activation. NO generation was implicated in the actions of several nephrotoxicants, i.e., diatrizoate, gentamicin, amikacin, HgCl2, and CdCl2, each of which decreased Mrp2-mediated transport by activating ET signaling. For each nephrotoxicant, decreased FL-MTX transport was prevented when tubules were exposed to L-NMMA. ET-1 and each nephrotoxicant stimulated NO production by the tubules, as determined by a fluorescence-based assay. Together, the data show that NO generation follows ET binding to the basolateral ETB receptor and that, in activating the ET-signaling pathway, nephrotoxicants produce NO, a molecule that could contribute to subsequent toxic effects.
multidrug resistance-associated protein 2; calcium; endothelin signaling; protein kinase C; xenobiotic transport; nitric oxide
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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METABOLISM AND EXCRETION provide a first line of defense against the wide variety of potentially toxic chemicals to which we are continually exposed. In the kidney, the proximal tubule is responsible for the excretory transport from blood to urine of xenobiotics, xenobiotic metabolites, and waste products of metabolism. As a result of its rich transport function, the proximal tubule is also an important target for toxic effects (2, 27).
To accomplish this excretory function, epithelial cells in the proximal tubule possess multiple plasma membrane transporters that use ATP and transmembrane ion gradients to drive active drug secretion into urine. Among the proteins implicated in this process is a member of the ATP-binding cassette superfamily of membrane transporters: multidrug resistance protein 2 (Mrp2). This transport protein is present at high levels in the luminal membrane of proximal tubule cells and handles a wide range of chemicals, from large, lipophilic organic anions to polypeptides (12, 22).
Using intact killifish (Fundulus heteroclitus) renal proximal tubules, a fluorescein methotrexate (FL-MTX) derivative, and confocal microscopy, we recently demonstrated that Mrp2 was regulated by endothelin (ET), which acted through a basolateral ETB receptor and protein kinase C (PKC) (13). By activating this signaling pathway, ET rapidly decreased cell-to-lumen transport of the fluorescent Mrp2 substrate FL-MTX. Interestingly, a similar decrease in transport was seen when tubules were exposed to several known nephrotoxic drugs (aminoglycoside antibiotics and radiocontrast agents), and that decrease was found to be caused by activation of ET-ETB-PKC signaling (13, 25). The nephrotoxicants caused release of ET from the tubules, and the hormone acted by an autocrine mechanism to signal a decrease in Mrp2-mediated transport. ET release appeared to be Ca2+ dependent in that elevated medium Ca2+ triggered the pathway, and the effects of nephrotoxicants and elevated medium Ca2+ were abolished by nifedipine, a Ca2+ channel blocker (25).
The precise sequence of events by which ET regulates Mrp2 transport is unclear. However, there is reason to believe that nitric oxide (NO) could be part of this ET-signaling cascade in the kidney (18). NO is produced by NO synthase (NOS). Both NOS and ET were found to be localized to the same nephron segments, including the proximal tubule (16, 18). In the vascular wall, it is well documented that ET can trigger the endothelial release of NO by means of stimulation of the ETB receptors (4, 5, 26). Recent data suggest comparable cross talk between ET and NO in renal tubular cells (19, 20). In addition, NO has been implicated in cyclosporin A- and FK506-induced nephrotoxicity in renal proximal tubules (6).
In the present study, we used killifish renal proximal tubules to demonstrate that release of NO is an intermediate step in ET signaling. The data also show that ET-activated NO production is also an early event in the action of nephrotoxicants, thus providing a possible mechanistic link between signaling and toxicity.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chemicals. The chemicals included FL-MTX, bisindolylmaleide (BIM), NG-monomethyl-L-arginine (L-NMMA), 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM) diacetate (Molecular Probes, Eugene, OR); RES-701-1, an ETB-receptor antagonist (Peninsula Laboratories, Belmont, CA); sodium nitroprusside (SNP; Calbiochem, San Diego, Ca); and HgCl2, CdCl2, gentamicin, amikacin, and diatrizoic acid (Sigma, St. Louis, MO). All other chemicals were obtained at the highest purity available.
Animals and tissue preparation. Killifish were collected by local fishermen in the vicinity of Mount Desert Island, ME, and maintained at the Mount Desert Island Biological Laboratory in tanks with natural flowing seawater. Renal tubular masses were isolated in a marine teleost saline, based on that of Forster and Taggart (3), containing (in mM) 140 NaCl, 2.5 KCl, 1.5 CaCl2, 1.0 MgCl2, and 20 Tris at pH 8.0. All experiments were carried out at 18-20°C. Under a dissecting microscope, each mass was teased with fine forceps to remove adherent hematopoietic tissue. Individual killifish proximal tubules were dissected and transferred to a foil-covered Teflon chamber (Bionique) containing 1.5 ml of marine teleost saline with 1 µM FL-MTX and added effectors. The chamber floor was a 4 × 4-cm glass coverslip to which the tubules adhered lightly and through which the tissue could be viewed by means of an inverted microscope. Tubules were incubated at room temperature for 30 min until steady state was reached for FL-MTX. Analysis of tubule extracts by high-performance liquid chromatography showed no metabolic degradation of FL-MTX when killifish proximal tubules were incubated for periods of at least 1 h (12, 23).
Confocal microscopy. The chamber containing renal tubules was mounted on the stage of an Olympus FluoView inverted confocal laser scanning microscope and viewed through a ×40 water-immersion objective (numerical aperature 1.15). Excitation was provided by the 488-nm line of an argon ion laser. A 510-nm dichroic filter and 515-nm long-pass emission filter were used. Neutral density filters and low laser intensity were used to avoid photobleaching. With the photomultiplier gain set to give an average luminal fluorescence intensity of 1,500-3,000 (on a scale of 0-4,096), tissue autofluorescence was undetectable. To obtain an image, dye-loaded tubules in the chamber were viewed under reduced, transmitted light illumination, and a single proximal tubule with well-defined lumen and undamaged epithelium was selected. The plane of focus was adjusted to cut through the center of the tubular lumen, and an image was acquired by averaging four scans. The confocal image was viewed on a high-resolution monitor and saved to an optical disk or Zip disk (Iomega). In previous studies, it has been shown that there is a linear relationship between fluorescence intensity and dye concentration (15). However, because of the many uncertainties in relating cellular fluorescence to actual compound concentration in cells and tissues with complex geometry, data are reported here as average measured pixel intensity rather than estimated dye concentration. Fluorescence intensities were measured from stored images using Scion image version 1.8 for Windows (12, 14). Briefly, two or three adjacent cellular and luminal areas were selected from each tubule, and the average pixel intensity for each area was calculated. The values used for that tubule were the means of all selected areas.
NO production by tubules was measured using an indicator, DAF-FM, that increases fluorescence intensity on exposure to NO. For the experiments, tubules were loaded for 1 h in medium containing 10 µM DAF-FM diacetate. This nonfluorescent derivative is membrane permeant and, on entering cells, is hydrolyzed to DAF-FM. After loading, tubules were transferred to confocal chambers containing medium without (control) and with effectors. After 5 min, confocal images were collected (as for FL-MTX) and saved to a Zip disk. Average tubule fluorescence was measured from the stored images as described above.Data analysis. Values are given as means ± SE. Mean values were considered to be significantly different when P < 0.05, by use of the unpaired t-test, or by a one-way ANOVA followed by Bonferroni's multiple comparison test. Software used for statistical analysis was GraphPad Prism (version 3.00 for Windows; GraphPad Software, San Diego, CA).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present experiments were conducted using isolated renal
proximal tubules from a marine teleost fish, the killifish. This has
proven a powerful model for the study of secretory transport in an
intact proximal tubule (21). As in mammalian proximal tubules, killifish express high levels of Mrp2 in the luminal membrane
of renal proximal tubule cells. Moreover, intact killifish tubules
exhibit Mrp2-mediated transport of a number of fluorescent substrates,
e.g., FL-MTX, that can be visualized and measured using confocal
microscopy (12-14). Figure
1A shows a typical confocal image of a control killifish tubule after 30-min (steady-state) incubation in medium with 1 µM FL-MTX. The fluorescence distribution pattern is the same as that shown previously, i.e., fluorescence intensity in lumen > cells > medium (12, 13).
We have demonstrated that this pattern is indicative of a two-step
process involving uptake at the basolateral membrane mediated by an as
yet uncharacterized transporter for large organic anions and secretion
into the lumen mediated by a teleost form of Mrp2 (for data on
substrate and inhibitor specificities as well as immunostaining with
Mrp2 antibodies, see Refs. 13 and 25).
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Figure 1 also shows confocal images of FL-MTX transport in tubules
exposed to the NO donor SNP. In previous experiments using ET-1, a
decrease in luminal accumulation of FL-MTX and no effect on cellular
accumulation have been taken to indicate decreased transport on Mrp2
(13). Similar to the effects of ET-1, 100 µM SNP
decreased luminal, but not cellular, accumulation of FL-MTX (Fig.
1B). Quantitation of images showed that 50-100 µM SNP
reduced steady-state luminal accumulation of FL-MTX by about 50% (Fig. 2A). The action of SNP was
rapid, causing a significant reduction of luminal fluorescence within
10 min of exposure and a sustained decrease over the 30-min experiment
(Fig. 2B). SNP did not affect cellular fluorescence.
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Figures 1 and 2 indicate that SNP and ET-1 have similar effects
on Mrp2-mediated transport of FL-MTX. To determine whether NO release
was a consequence of ET-1 exposure, tubules were exposed to 10 nM ET-1
in the absence or presence of L-NMMA, an NOS inhibitor. Figure 3 shows that L-NMMA by
itself had no effect on FL-MTX transport but attenuated the effect of
ET-1. Thus ET-1 activated NOS. In killifish tubules, ET-1 interacts
with a basolateral ETB receptor and reduces Mrp2-mediated
transport by acting through PKC (13). In this study the
effects provided by ET-1 were prevented using the ETB
receptor-antagonist RES-701-1 or PKC-selective inhibitors BIM,
calphostin C, or staurosporine. To determine where NO generation was
placed in the signaling pathway, we examined the abilities of
RES-701-1 and the PKC-selective inhibitor BIM to attenuate the
effects of SNP on FL-MTX transport. RES-701-1 did not alter the
effects of SNP on transport (Fig.
4), but BIM protected completely (Fig.
5), indicating that NO generation came
after ETB receptor binding but before PKC activation.
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We recently found that ET release and subsequent signaling in
killifish tubules could be activated by two types of external stimuli:
elevated extracellular Ca2+ and several structurally
unrelated nephrotoxicants (25). The present experiments
indicate that each acts through NO. Figure 6 shows that L-NMMA prevented
the decrease in luminal FL-MTX accumulation caused by increasing the
medium Ca2+ concentration from 1.5 mM in controls to 3 mM
in treated tubules. Table 1 shows the
results of a series of experiments in which nephrotoxicants reduced
FL-MTX transport mediated by Mrp2. The data for the aminoglycoside
antibiotics gentamicin and amikacin and for the radiocontrast agent
diatrizoate confirm previous findings (25). For these
drugs, effects on Mrp2-mediated transport were shown to be caused by
stimulation of ET release by the tubules and subsequent ET action
through the ETB receptor and PKC (25). Additional experiments with killifish tubules have disclosed a similar
mechanism of action for low concentrations of heavy-metal salts
HgCl2 and CdCl2 (Terlouw SA and Miller DS,
unpublished observations). Table 1 shows that, for all these
nephrotoxicants, including HgCl2 and CdCl2,
inhibition of NOS by L-NMMA prevented the reduction in
Mrp2-mediated transport. Thus the effects of elevated medium Ca2+ and the nephrotoxicants appear to involve generation
of NO.
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To test this supposition directly, we used a fluorescence-based
technique to measure NO generation in intact killifish tubules. The
technique relies on the formation of a highly fluorescent product when
DAF-FM reacts with NO. The indicator is introduced to the tubule as a
nonfluorescent ester, DAF-FM diacetate, which is membrane permeable and
hydrolyzed intracellularly to DAF-FM. Figure
7 shows that the average fluorescence
intensity was low in control tubules but increased by several times in
tubules exposed to SNP (100 µM). Roughly the same magnitude of
increase was also found for tubules exposed to diatrizoate,
CdCl2, amikacin, and gentamicin at concentrations that
reduce FL-MTX transport mediated by Mrp2. ET-1 also generated NO (Fig.
8A), and this production was
blocked by the NOS inhibitor L-NMMA. Finally, Fig.
8B shows that NO production induced by gentamicin was
blocked by the ETB receptor antagonist RES-701-1.
Together these data demonstrate that ET-1 and the nephrotoxicants
stimulated NO production in the tubules.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Using killifish renal proximal tubules, we previously demonstrated
that ET, acting through an ETB receptor and PKC, reduced transport mediated by Mrp2, i.e., luminal accumulation of FL-MTX (13). In the present study, we used Mrp2-mediated
transport of FL-MTX to monitor activity of this ET-fired, intracellular signaling pathway; the purpose was to examine further the chain of
events that connect ETB receptor binding at the basolateral membrane to reduction of transport at the luminal membrane. We show
here that exposing tubules to SNP, an NO donor, also signaled a
reduction in transport. Importantly, exposure to L-NMMA, an NOS inhibitor, blocked the action of ET-1 on transport. Because the
effects of SNP on transport were blocked by BIM, a PKC selective inhibitor, but not by RES-701-1, an ETB receptor
antagonist, generation of NO occurred after receptor signaling but
before PKC activation. Several additional observations are consistent
with this proposed sequence of events. Experiments using a
fluorescence-based NO assay showed that ET-1 and the nephrotoxicants
stimulated NO production by intact tubules. For ET-1, NO production was
blocked by an inhibitor of NOS; for the nephrotoxicant, gentamicin, NO
production was blocked by an ETB receptor antagonist. A
scheme of the proposed signaling pathway is shown in Fig.
9.
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The present data are the first to describe an ET-NO-PKC signaling axis in renal proximal tubules. In agreement with our findings, activation of NOS was found after ETB receptor stimulation in the thick ascending limb, and this was associated with inhibited chloride transport (19, 20). In OK cells, an opossum kidney proximal tubule cell line, Liang and Knox (9) described an NO-PKC-Na+,K+-ATPase signaling pathway. Such a pathway was not present in LLC-PK1 cells, a proximal tubule cell line from pig (9). Obviously, species differences or differences in culture conditions could underlie the differences in signaling found in the two cell lines.
Liang and Knox (9) have suggested that NOS might activate PKC through guanylate cyclase. Results indicating cGMP generation after NO synthesis confirm this suggestion (24, 30). Interestingly, it was recently shown that one member of the MRP family, viz. MRP5, transports cGMP (7). It is possible that Mrp2 transports the cyclic nucleotide as well, and cGMP might compete with FL-MTX for efflux, resulting in a decreased FL-MTX transport. In this regard, our preliminary experiments show that, in killifish tubules, 8-bromoguanosine 3',5'-cyclic monophosphate is a potent inhibitor of FL-MTX transport from cell to lumen, and at least a portion of that inhibition is removed when tubules are pretreated with an inhibitor of protein kinase G (Notenboom S and Miller DS, unpublished observations). The latter suggests activation of guanylate cylclase by PKC rather than the opposite, because the effect of NO generation by the NO donor SNP was completely reversed by inhibiting PKC. Whether guanylate cyclase is directly or indirectly responsible for a diminished transport of organic anions by Mrp2 will be investigated in further research.
Although it is not clear whether proximal tubules are capable of generating NO under basal conditions, they certainly can produce large amounts of the substance when stimulated (10). In this regard, proximal tubules express several NOS isoforms, including inducible and endothelial NOS, and NO production increases on exposure to a variety of stimuli, including lipopolysaccharide, cytokines, hypoxia, and several nephrotoxic chemicals (10). The present results indicate that, when killifish proximal tubules were exposed to radiocontrast agents, aminoglycoside antibiotics, or heavy-metal salts, NO production increased. In addition, Mrp2-mediated transport decreased for each compound and these decreases were prevented when the tubules were also exposed to an NOS inhibitor, L-NMMA. We have recently found that each tested nephrotoxicant reduced Mrp2-mediated transport in killifish tubules by inducing ET release and activating ETB receptor-PKC signaling (13, 25). Nephrotoxicant action appeared to be Ca2+ dependent, because nifedipine, an L-type Ca2+ channel blocker, protected its action and because elevated medium Ca2+ also stimulated ET release and signaling. The present results indicate that exposure of tubules to nephrotoxicants or elevated medium Ca2+ also produces NO as an intermediate step in signaling (Fig. 9).
Production of NO as a consequence of nephrotoxicant-triggered signaling provides a toxicological context in which to consider the present and previous results. NO production has been implicated in renal diseases and the action of several nephrotoxic compounds (8). For example, hypoxic/ischemic injury is prevented by NG-nitro-L-arginine methyl ester and enhanced by SNP (29), and inducible NOS appears to be the critical isoform involved (11, 17). In renal proximal tubule cells, NO induces apoptosis and potentiates immunosupressant-induced apoptosis (1, 6). ET signaling and NO production are implicated in HgCl2-induced acute renal failure (28). In this regard, although short-term exposure of killifish tubules to the relatively low concentrations of nephrotoxic compounds used in the present study produced no evidence of cellular toxicity [as measured by the ability to actively transport fluorescein on the classical organic anion system (Ref. 25 and Notenboom S. and Miller DS, unpublished observations)], our initial experiments show that longer exposures are clearly toxic and that L-NMMA can protect (Notenboom S and Miller DS, unpublished observations). Experiments are under way to determine whether toxicity is a result of signaling through the ET-ETB receptor-NOS-PKC pathway or whether a separate sequence of events leads to NO production and subsequent toxicity.
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ACKNOWLEDGEMENTS |
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This study was supported by travel grants from the Dutch Kidney Foundation and Dr. S. van Zwanenbergstichting.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. Masereeuw, Dept. of Pharmacology and Toxicology 233, Univ. Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands (E-mail: R.Masereeuw{at}ncmls.kun.nl).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajprenal.00173.2001
Received 31 May 2001; accepted in final form 11 October 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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 J. Goddard, N. R. Johnston, A. D. Cumming, and D. J. Webb Fractional urinary excretion of endothelin-1 is reduced by acute ETB receptor blockade Am J Physiol Renal Physiol, November 1, 2007; 293(5): F1433 - F1438. [Abstract] [Full Text] [PDF]
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K. E. Wever, R. Masereeuw, D. S. Miller, X. M. Hang, and G. Flik Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport Am J Physiol Renal Physiol, January 1, 2007; 292(1): F38 - F46. [Abstract] [Full Text] [PDF]
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 C. Zeng, U. Hopfer, L. D. Asico, G. M. Eisner, R. A. Felder, and P. A. Jose Altered AT1 Receptor Regulation of ETB Receptors in Renal Proximal Tubule Cells of Spontaneously Hypertensive Rats Hypertension, October 1, 2005; 46(4): 926 - 931. [Abstract] [Full Text] [PDF]
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 B. Bauer, A. M. S. Hartz, G. Fricker, and D. S. Miller Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier Experimental Biology and Medicine, February 1, 2005; 230(2): 118 - 127. [Abstract] [Full Text] [PDF]
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 S. H. Wright and W. H. Dantzler Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport Physiol Rev, July 1, 2004; 84(3): 987 - 1049. [Abstract] [Full Text] [PDF]
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S. Notenboom, D. S. Miller, P. Smits, F. G. M. Russel, and R. Masereeuw Involvement of guanylyl cyclase and cGMP in the regulation of Mrp2-mediated transport in the proximal tubule Am J Physiol Renal Physiol, July 1, 2004; 287(1): F33 - F38. [Abstract] [Full Text] [PDF]
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 S. A. Terlouw, C. Graeff, P. H. E. Smeets, G. Fricker, F. G. M. Russel, R. Masereeuw, and D. S. Miller Short- and Long-Term Influences of Heavy Metals on Anionic Drug Efflux from Renal Proximal Tubule J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 578 - 585. [Abstract] [Full Text] [PDF]
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