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From the
Received for publication, October 15, 2001
Aminoglycosides are antibiotics commonly used to
treat life-threatening Gram-negative bacterial infections. However,
their use is hampered by their severe nephrotoxicity due to
accumulation in renal proximal tubules. Several pathways have been
implicated in the renal uptake of aminoglycosides including megalin, an
endocytic receptor in proximal tubular cells. Here, we have used mouse
models with genetic or functional megalin deficiency to explore the
contribution of megalin and other pathways to renal aminoglycoside
uptake in vivo. We demonstrate that the uptake of
aminoglycosides into the kidney directly correlates with renal megalin
activity and is completely eliminated in mice lacking the receptor.
Thus, our studies provide unequivocal evidence that megalin is the only major pathway responsible for renal aminoglycoside accumulation and
that the receptor represents a unique drug target to prevent aminoglycoside-induced nephrotoxicity in patients.
Aminoglycosides are among the most commonly used antibiotics
worldwide. They are active against a wide range of Gram-negative bacteria, including Pseudomonas, Enterobacter,
Proteus, and Neisseria species. Because of their
effectiveness and the low rate of true resistance, aminoglycosides are
often considered the drug of choice to treat life-threatening
infections such as bacterial endocarditis, peritonitis, and sepsis, as
well as tuberculosis. Their relatively low costs make them attractive,
particularly in developing countries. The clinical importance of
aminoglycosides is likely to increase in the future due to the rapid
rise in pathogens resistant to other classes of antibiotics (1, 2).
The main obstacle in the clinical use of aminoglycosides is their
severe nephro- and ototoxicity. Aminoglycosides specifically accumulate
in epithelial cells of the renal proximal tubule and in hair cells of
the inner ear causing a variety of deleterious effects and eventual
cell death (3-9). In recent years, changes in treatment regimens such
as single daily dosing and monitoring procedures reduced the risk
associated with aminoglycoside therapy. Nevertheless, still up to 10%
of patients suffer from the toxic side effects of these antibiotics (1,
2).
When applied systemically, aminoglycosides remain largely inert. They
do not adhere to plasma proteins and are eliminated from the body
through glomerular filtration. After 24 h, 70-90% of the
antibiotic has been excreted into the urine. In general, the tissue
penetrance of aminoglycosides is low, with the exception of the renal
cortex that may absorb up to 5% of the compound. There,
aminoglycosides persist for a long time (half-life > 100 h)
causing renal damage (10).
Because the accumulation of aminoglycosides in epithelial cells of the
proximal tubules is the main factor determining their nephrotoxicity,
much attention had been focused on the identification of pathways
responsible for cellular aminoglycoside uptake. Fluid phase uptake,
adsorptive binding, and clearance by low affinity sites or
receptor-mediated endocytosis all have been held responsible for renal
aminoglycoside accumulation (7, 8). Among other pathways, megalin, an
endocytic receptor expressed on the apical surface of the proximal
tubular epithelium, has been implicated in renal aminoglycoside uptake
(11, 12). Megalin constitutes the main endocytic pathway for clearance
of low molecular weight plasma proteins from the glomerular filtrate
(13). In megalin-deficient mice, lack of this uptake pathway results in
tubular resorption deficiency and low molecular weight proteinuria
(14). Physiological ligands taken up by megalin include insulin (15),
transthyretin (16), and carriers for lipophilic vitamins, the vitamin
D-binding protein (17) and the retinol-binding protein (18).
Besides the uptake of filtered plasma proteins, megalin may also be
responsible for the clearance of xenobiotic compounds from the primary
urine. In particular, polybasic substances such as aminoglycosides may
interact with abundant negative charges on the extracellular receptor
domain thereby gaining entrance to proximal tubular cells (11). Several
studies in the rat, an animal model of aminoglycoside-induced
nephrotoxicity, have addressed a possible role of megalin in renal
aminoglycoside uptake. Moestrup et al. (11) used a
specific megalin antagonist, the receptor-associated protein
(RAP),1 to block the activity
of the receptor in perfused rat proximal tubules. Inhibition of megalin
reduced the clearance of gentamicin by ~20% (11). Nagai et
al. (19) analyzed the aminoglycoside clearance in rats treated
with maleate. This substance causes shedding of megalin from the
brush-border surface, thus impairing receptor-mediated ligand uptake.
In maleate-treated animals, the tubular clearance of aminoglycosides
was decreased to the same extent as that of megalin ligands, suggesting
uptake via the same receptor pathway (19).
While some experimental evidence links megalin activity with tubular
uptake of aminoglycosides in the rat, the quantitative contribution of
the receptor to renal aminoglycoside accumulation remained unclear. So
far, inhibitors used to interfere with megalin activity were only
marginally effective in blocking aminoglycoside clearance
(e.g. RAP) or may have had additional unspecific effects on
other tubular uptake pathways (e.g. maleate). Furthermore, studies by others suggested that renal aminoglycoside uptake also proceeds from the basolateral surface of the tubules (20) or that
uptake is independent of endocytosis (21, 22).
Mice with genetically induced megalin deficiencies represent unique
model systems to test a role of megalin in uptake of aminoglycoside into the kidney. Here, we have used two mouse models with induced receptor defects to dissect the quantitative contribution of megalin and other pathways to renal aminoglycoside accumulation. We demonstrate that aminoglycoside uptake into the kidney correlates with renal megalin activity and is absent in mice lacking the receptor (megalin knockout mice). As such, our studies provide clear evidence that megalin is the only major pathway for renal accumulation of aminoglycosides.
Gentamicin Turnover in Mice--
Wild type and megalin-deficient
mice (C57BL/6J × 129SvJ hybrids) were bred in house;
RAP-deficient mice (C57BL/6J) were purchased from the Jackson
Laboratories (www.jax.org). [3H]Gentamicin (58.1 GBq/mmol) was obtained from Amersham Biosciences, Inc.
(www.apbiotech.com); gentamicin was purchased from Sigma (www.sigma-aldrich.com). For application in mice,
[3H]gentamicin was diluted in 50 mM Tris, 150 mM NaCl, pH 7.4, and injected intraperitoneally or
intravenously at a dose of 2.2 × 105 dpm/g body
weight (45 µg of gentamicin/kg). Then, the animals were placed in
metabolic cages for urine collection. At the end of the experiment,
blood was sampled by retroorbital puncture, and the animals were killed
by cervical dislocation. Organs were collected, weighed, and
homogenized for 45 s in 10 ml of H2O. 500 µl of
homogenate were added to 10 ml of scintillation fluid (ReadySafe,
Beckman; www.beckman.com) and counted. The statistical significance of
values was determined by Student's t test.
Autoradiography--
[3H]Gentamicin was injected
intraperitoneally into laboratory animals at a dose of 2.2 × 106 (mice) or 7.2 × 106 (rats) dpm/g body
weight. After 24 h, the kidneys were fixed by retrograde perfusion
through the abdominal aorta using 1% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.4, postfixed, dehydrated, and embedded in Epon. Unless indicated otherwise, the tissues were
prepared for light microscope autoradiography on 1-µm Epon sections
using Ilford K2 emulsion. The sections were exposed for 2-4 weeks. For
electron microscope autoradiography, Ilford L4 emulsion was applied to
60-nm sections as described (23). The sections were exposed for 2-4 months.
Previous studies on the renal metabolism of aminoglycosides have
mainly focused on the rat because this animal model exhibits similar
susceptibility to aminoglycoside-induced nephrotoxicity as patients (3,
24-27). In contrast, for reasons largely unknown mice are resistant to
aminoglycoside nephrotoxicity (24, 25). To ensure that murine
resistance to nephrotoxicity was not due to differences in the renal
handling of aminoglycosides as compared with patients and rats, we
initially characterized the metabolism of gentamicin in wild type mice.
We injected [3H]gentamicin intraperitoneally into the
animals and determined the distribution of the tracer in plasma, urine,
and tissues 24 h later. As seen in Fig.
1, 10% of the tracer was recovered in the kidneys, whereas 45% was found in the urine. No significant amounts of radioactivity were detected in any other tissue. Thus, the
remainder of the tracer was most likely lost in the metabolic cages
used for urine collection. The renal uptake of
[3H]gentamicin was rapid with 10% of the tracer
accumulating in the kidneys as early as 30 min after drug
administration (Fig. 2A). The
radioactivity persisted in the kidneys for more than 24 h and
slowly declined thereafter (Fig. 2A). Still after 148 h, 3.4% of the tracer resided in the kidneys (data not shown). The
kinetics of renal uptake was identical regardless of whether the tracer
was applied intraperitoneally (Fig. 2A) or intravenously (data not shown).
One of the hallmarks of renal aminoglycoside uptake in rats and
patients is concentration dependence and saturability at clinically relevant doses (2-6 mg/kg in patients) (28). The same effect was
observed in the mouse (Fig. 2B). When
[3H]gentamicin was injected together with increasing
concentrations of unlabeled gentamicin, the renal uptake of the tracer
decreased accordingly. Half-saturating concentrations for gentamicin
were reached at ~5 mg/kg body weight. As shown by autoradiography, the tracer specifically accumulated in the renal cortex of the mice
(Fig. 3). To further characterize this
uptake pathway at the cellular level, we compared the renal
distribution and subcellular localization of
[3H]gentamicin in mice and rats. In both animal models,
[3H]gentamicin was detected exclusively in proximal
tubular cells (Fig. 4, C and
D). No tracer was seen in any other renal cell type (Fig. 4,
A and B). In mice, the autoradiographic signal
for [3H]gentamicin was concentrated in the apical
cytoplasm (Fig. 4B). In contrast, in proximal tubules of the
rat the tracer was more evenly distributed throughout the interior of
the cells (Fig. 4A). This observation is consistent with an
accumulation of gentamicin in lysosomes in both species because these
vesicles are localized in the subapical space in mouse tubules and
found deeper in the cytoplasm in the rat (13). The presence of the
antibiotic in identical lysosomal compartments of rat and mouse cells
was finally confirmed by autoradiography of electron micrographs (Fig.
5). No difference in the subcellular
distribution of the tracer was observed between the species (Fig.
5).
Megalin Deficiency Offers Protection from Renal
Aminoglycoside Accumulation*
,,,
, and**
Max-Delbrueck-Center for Molecular
Medicine and ** Medical Faculty of the Free University of
Berlin, Berlin D-13125, Germany, Franz-Volhard-Clinic,
Medical Faculty of the Humboldt University of Berlin, Berlin
D-13125, Germany, and Departments of § Medical Biochemistry
and ¶ Cell Biology, University of Aarhus, DK-8000 Aarhus,
Denmark
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
View larger version (17K):
[in a new window]
Fig. 1.
Accumulation of [3H]gentamicin
in mouse tissues. Wild type mice were injected intraperitoneally
with [3H]gentamicin (45 µg/kg) and placed in metabolic
cages for urine collection. After 24 h, the amount of
radioactivity in urine, in plasma, and in the indicated tissues was
quantified. The values represent the mean (± S.E.) of five animals and
are given as percent of the injected dose.
View larger version (13K):
[in a new window]
Fig. 2.
Pharmacokinetics of
[3H]gentamicin uptake into mouse kidneys.
A, wild type mice were injected intraperitoneally with
[3H]gentamicin (45 µg/kg). At the indicated time
points, kidney samples were collected, and the amount of radioactivity
taken up into the tissue was determined. B, wild type mice
were injected intraperitoneally with [3H]gentamicin (45 µg/kg) together with the indicated concentrations of unlabeled
gentamicin. The amount of radioactivity in the kidneys was determined
24 h later. Values are the mean ± S.E. of 3-10
animals.
View larger version (147K):
[in a new window]
Fig. 3.
Autoradiographic detection of
[3H]gentamicin in mouse kidneys. Mice were injected
intraperitoneally with 2.2 × 106 dpm/g of
[3H]gentamicin. Kidney samples were collected after
24 h and processed for routine cryosectioning and autoradiography
as described under "Experimental Procedures." Exposure time of the
tissue section (10 µm) was 5 days. The arrows indicate
[3H]gentamicin accumulation in the renal cortex.
(magnification ×25).
View larger version (124K):
[in a new window]
Fig. 4.
Comparative analysis of
[3H]gentamicin accumulation in rat (A
and C) and mouse kidneys (B and
D). Rats and mice were injected intraperitoneally
with 7.2 × 106 and 2.2 × 106 dpm/g
of [3H]gentamicin, respectively. Kidneys were collected
after 24 h and processed for routine cryosectioning and
autoradiography of medullary (A and B) and
cortical (C and D) tissue sections. Accumulation
of gentamicin was detected in proximal tubules of the renal cortex in
rats (C) and mice (D) but not in the medulla of
both species (A and B). Exposure time of the
tissue sections was 4 weeks (scale bars, 40 µm in
A and B; 20 µm in C and
D).
View larger version (111K):
[in a new window]
Fig. 5.
Subcellular localization of
[3H]gentamicin in lysosomes of rat (A)
and mouse (B) proximal tubular cells. Rats and
mice were injected with [3H]gentamicin as described in
the legend to Fig. 4. Kidneys were collected after 24 h and
processed for routine electron microscopy and autoradiography.
Autoradiographic grains are seen exclusively over lysosomes of rat
(A) and mouse (B) proximal tubular cells.
Exposure time of the tissue sections was 4 months. E,
endosomes; L, lysosomes (scale bar, 0.5 µm).
So far, our studies had demonstrated that the metabolism and cellular
uptake of gentamicin in mice exhibits the same characteristics as in
humans and rats. Therefore, the mouse constituted an appropriate animal
model to study the common molecular pathways involved in renal
aminoglycoside accumulation. To determine the quantitative contribution
of megalin and other pathways to renal aminoglycoside uptake in
vivo, we compared the pharmacokinetics of
[3H]gentamicin in wild type and megalin-deficient mice.
In wild type animals, 10.6 ± 0.5% (mean ± S.E.) of the
tracer accumulated in the kidneys 24 h after drug administration;
46.9 ± 3.4% was excreted into the urine (Fig.
6). Megalin-deficient mice excreted similar amounts of the tracer (38.2 ± 8.6%), suggesting
identical glomerular filtration rates. However, receptor-deficient
animals did not exhibit any significant [3H]gentamicin
accumulation in their kidneys (0.6 ± 0.1%, Fig. 6). This effect
was not due to a metabolic turnover of aminoglycosides by expression of
the neomycin phosphotransferase gene used for megalin gene targeting
because mice carrying unrelated gene knockouts were indistinguishable
from wild type controls (renin-binding protein knockout, Fig. 6).
|
To confirm that the rate of aminoglycoside accumulation directly
correlated with the amount of megalin in the kidney, we tested the
turnover of [3H]gentamicin in a mouse model of reduced
receptor expression. In mice genetically deficient for RAP, the amount
of megalin in the kidney is reduced by ~50% as compared with wild
type animals (Fig. 7, inset).
The reduction in megalin expression is most pronounced when the animals
are kept on a C57BL/6J genetic background (29, 30). RAP is a cellular
chaperone that blocks binding of ligands to the receptor and is
required for proper biosynthesis and intracellular transport of megalin
(29, 31). Consequently, in mice lacking this chaperone, the
biosynthetic pathway of the receptor is disrupted resulting in
decreased expression levels (29, 30). To be able to detect subtle
differences in renal aminoglycoside uptake in RAP knockout
versus wild type mice, we injected
[3H]gentamicin together with 30 mg/kg unlabeled
gentamicin (saturating concentrations, see Fig. 2B).
Consistent with a reduction in receptor levels, the amount of
[3H]gentamicin in RAP
/ kidneys was
decreased by ~50% as compared with control tissues (p < 0.001, Fig. 7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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Here, we have demonstrated that megalin, an endocytic receptor in
the renal proximal tubules, represents the only major pathway for
accumulation of aminoglycosides in the mouse kidney. Renal uptake of
the antibiotic directly correlates with the levels of receptor activity
in mouse models of reduced megalin function (RAP/, Fig.
7). No renal uptake of aminoglycosides can be observed in mice
completely devoid of the receptor (megalin/, Fig. 6).
This lack of uptake is a direct consequence of the megalin deficiency
and is not caused by unspecific kidney defects because renal functions
such as glomerular filtration, urine output, or tubular resorption of
electrolytes and other metabolites are normal in
megalin/ animals (14). The identification of an
endocytic pathway responsible for cellular uptake of aminoglycosides
confirms earlier findings that localized these antibiotics within
endosomes and lysosomes of proximal tubular cells (27, 32). In
contrast, our results argue against a significant role of other routes
such as fluid phase uptake or non-endocytic pathways in entry of
aminoglycosides into cells in vivo. Because megalin is
exclusively present on the apical membranes of the tubular epithelium
(33, 34), in vivo uptake of aminoglycosides from the
basolateral surface into tubular cells also seems less likely.
Previous studies on the role of megalin in renal aminoglycoside accumulation focused on the rat as a model system (11, 19). Megalin antagonists were used to interfere with the activity of receptor and to test the consequences for aminoglycoside uptake in vivo. In these studies, RAP reduced the tubular clearance of gentamicin by 20% suggesting a minor role of megalin in renal aminoglycoside accumulation (11). Contrary to the rat, mouse models with induced megalin deficiencies represent the first genetically defined animal models to quantify the contribution of megalin to renal aminoglycoside uptake. In these models, megalin represents the only major pathway for aminoglycoside uptake and lack of the receptor offers protection from renal accumulation of the antibiotic. The moderate effect of RAP on gentamicin uptake observed in the rat is not due to differences in aminoglycoside uptake pathways in this animal model as compared with the mouse. Rather, the ineffectiveness of this inhibitor is explained by its inability to efficiently interfere with gentamicin binding to megalin. Approximately 60-100 molecules of gentamicin bind per megalin molecule whereas RAP occupies only 1-2 ligand binding sites on the receptor.2 Therefore, the antagonist is largely ineffective in blocking gentamicin binding to megalin.
It is well established that renal uptake of aminoglycosides is the main factor that determines their nephrotoxicity. Thus, aminoglycoside derivatives with reduced tendency to accumulate in the renal cortex also proved less nephrotoxic (35). Given its central role in renal aminoglycoside uptake, megalin activity can be assumed to be a critical factor contributing to aminoglycoside-induced nephrotoxicity. Conceivably, functional megalin deficiency should prevent nephrotoxic side effects of aminoglycoside treatment. Unfortunately, the resistance of mice to aminoglycoside-induced nephrotoxicity precludes testing of this hypothesis in our mouse models. Even after prolonged exposure of wild type mice to high doses of gentamicin, we have not been able to detect major signs of tubular damage. Similar findings were also seen by others (24, 25). The reasons for this resistance remain unknown. To confirm that the insensitivity of mice to aminoglycosides is not due to the existence of different uptake routes, we compared renal gentamicin clearance in mice and rats. All parameters including plasma and renal half-life, tissue distribution, concentration dependence, and saturability of renal uptake were identical in both models. Moreover, gentamicin was detected in the same intracellular compartments (lysosomes) in rat and mouse proximal tubules. Taken together, these findings clearly demonstrate that identical pathways for aminoglycoside uptake exist in both species and that megalin is likely to play an equally crucial role in renal uptake and nephrotoxicity of aminoglycosides in rats and patients.
Accumulation of aminoglycosides in lysosomes with subsequent rupture of the vesicles is considered the main mechanism causing nephrotoxicity in rats and humans (7). Because aminoglycosides are directed to the very same organelles in mouse proximal tubules, murine resistance to aminoglycoside-induced nephrotoxicity likely involves alternative strategies of the mouse to deal with the consequences of intracellular aminoglycoside accumulation. Consistent with this hypothesis, specific protective mechanisms in the mouse to inactivate internalized aminoglycosides or to repair damaged renal tissues are being discussed (8). Elucidation of these mechanisms may reveal possible strategies also to deal with aminoglycoside accumulation in patients. These investigations are, however, beyond the scope of this study.
In conclusion, acute renal failure caused by aminoglycosides is still
an important clinical entity that hampers the unrestricted use of these
antibiotics. In industrialized nations, elaborate dosing and monitoring
procedures have been implemented to minimize toxic side effects of
aminoglycoside treatment. However, these measures result in a dramatic
increase in therapy costs. While a standard gentamicin therapy amounts
to only $20 for drugs, supplies, and labor costs, therapy requires an
additional $17 for monitoring and $180 for treatment of nephrotoxic
side effects (36, 37). In developing countries where no monitoring
procedures are implemented and aminoglycosides are often available
freely over the counter, side effects of aminoglycoside therapy
constitute a major health problem (38). Our studies now suggest a novel
approach to prevent aminoglycoside-induced toxicity using megalin
antagonists. All available data support the concept that filtrated
aminoglycosides adhere to this receptor that represents an abundant
surface area in the renal proximal tubule. Conceivably, receptor
antagonists that occupy the same binding sites on the receptor should
be effective in blocking tubular uptake of aminoglycosides.
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ACKNOWLEDGEMENTS |
|---|
We are indebted to C. Raeder, H. Schulz, H. Sidelmann, I. Kristoffersen, and A. Meier for expert technical assistance and to A. Nykjaer for critical reading of the manuscript.
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FOOTNOTES |
|---|
* This work was supported by the Deutsche Forschungsgemeinschaft, the Verbund Klinische Pharmakologie Berlin-Brandenburg, the Danish Medical Research Council, the NOVO-Nordisc Foundation, and the University of Aarhus.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.
To whom correspondence should be addressed:
Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany. Tel.: 49-30-9406-2569; Fax: 49-30-9406-3382; E-mail: willnow@mdc-berlin.de.
Published, JBC Papers in Press, November 7, 2001, DOI 10.1074/jbc.M109959200
1 The abbreviation used is RAP, receptor-associated protein.
2 J. Hilpert, C. Jacobsen, and T. E. Willnow, unpublished observations.
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REFERENCES |
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ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
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