Original article

Comparison of the transcellular transport of FDG
and D-glucose by the kidney epithelial cell line, LLC-PK1

Masato Kobayashia,b, Naoto Shikanoc, Ryuichi Nishiid, Yasushi Kiyonob,
Hiroyo Arakia, Kodai Nishia, Myungmi Ohe, Hiroyuki Okudairaa, Masato Ogurac,
Mitsuyoshi Yoshimotof, Hidehiko Okazawab, Yasuhisa Fujibayashib
and Keiichi Kawaia,b
Objectives Almost all D -glucose (GLU) filtered throughthe glomerulus is reabsorbed by the renal proximal
tubules, whereas a high portion of 2-[18F]fluoro-2-deoxy-D glucose [(18F)FDG] is excreted through the urine. However,[18F]FDG is not entirely excreted in the urine suggestingthat it may be partially reabsorbed by the proximal tubules.
The purpose of this study was to compare the time courseof transcellular transport of administered [14C] labeled
FDG ([14C]FDG) with that of [14C] labeled GLU ([14C]GLU)
using the kidney epithelial cell line, LLC-PK1.
Methods Transcellular transport of [14C]FDG and[14C]GLU by LLC-PK1 cells was measured in
Na + -containing or Na + -free Dulbecco’s phosphatebuffered saline [PBS( + ) and PBS( – ), respectively] in thepresence or absence of phlorizin, phloretin, probenecid, or
tetraethylammonium bromide inhibitors that predominantly
inhibit sodium-dependent glucose transporters (SGLTs),
sodium-independent glucose transporters, organic aniontransporters, and organic cation transporters, respectively.

90 min of incubation. Secretion of [14C]FDG also tended
to be slightly higher than that of [14C]GLU over 90 minof incubation.
Conclusion Transcellular transport of [14C]FDG overtime by LLC-PK1 cells was clarified. The polarized
distribution of transcellular transporters of [14C]FDG
and [14C]GLU in LLC-PK1 cells differs. Nucl Med Commun
31:141–146 c 2010 Wolters Kluwer Health | Lippincott
Williams & Wilkins.
Nuclear Medicine Communications 2010, 31:141–146
Keywords: D -glucose, fluoro-2-deoxy-D -glucose, kidney epithelial cell line
LLC-PK1, renal proximal tubule, transcellular transportaGraduate School of Medical Science, Kanazawa University, Kanazawa,
Biomedical Imaging Research Center, University of Fukui, Fukui, cDepartment ofRadiological Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki,dResearch Institute, Shiga Medical Center, Shiga, eDepartment ofOtorhinolaryngology, University of Fukui, Fukui and fNational Cancer Center,
Cancer Prevention Basic Research Project, Tokyo, Japanb

Results When assayed in PBS( + ), less [14C]FDG than
[14C]GLU was reabsorbed by the proximal tubular cells
over the entire incubation time. Reabsorption of [14C]FDG
was mediated mainly by SGLT at early time points in the
incubation, whereas high reabsorption of [14C]GLU was
mediated by both SGLT and glucose transporter overCorrespondence to Professor Keiichi Kawai, PhD, Graduate School of
Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa,
Ishikawa 920-0942, Japan
Tel: + 81 76 265 2527; fax: + 81 76 234 4366;e-mail: kei@mhs.mp.kanazawa-u.ac.jp

Introduction

transmembrane domains, and six subtypes (SGLT1–SGLT6)
of SGLTs have been identified [11]. The family of facilitative GLUTs comprises 13 members (GLUT1–GLUT13)[12]. The expression levels of SGLTs and GLUTs
have been shown to differ between certain tumor andnormal cells. The SGLTs and GLUTs display a polarized
distribution in renal proximal tubule cells that have anapical Na + -glucose cotransport system [13,14] that involves
SGLTs [15,16] and a basolateral Na + -independentfacilitated diffusion system that involves GLUTs [17,18].

The 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG)-positronemission tomography (PET) is commonly used for the
diagnosis, staging, measurement of treatment response,and management of patients with various types of malignancies [1–3]. The mechanism and biochemical pathwayof FDG uptake in cancer cells has been extensively
studied both in vitro [4] and in vivo [5,6]. [18F]FDG,
which is an analog of D-glucose (GLU), is taken up
into cells through the cell membrane through sodiumindependent glucose transport (GLUT) proteins [7,8],
and is then phosphorylated to [18F]FDG-6-phosphate byhexokinase inside the cell [9,10].
Glucose transport into mammalian cells is accomplishedby two classes of transporters: sodium-dependent GLUTs(SGLTs) and facilitative GLUTs. SGLTs consist of 140143-3636 c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Received 9 July 2009 Accepted 16 September 2009

A model of the glucose transport systems in the proximal
tubule of kidney epithelial LLC-PK1 cell line derived
from pig is shown in Fig. 1. This cell line has been usefulfor studying the polarized distribution of the transcellulartransporters SGLTs and/or GLUTs [15,19–21]. Thus, thiscell line exhibits a basolateral Na + -independent GLUT-1
DOI: 10.1097/MNM.0b013e328333bcf5

142 Nuclear Medicine Communications 2010, Vol 31 No 2

Fig. 1

Apical membrane
SGLT

GLUT

OAT

OCT

Reabsorption

Secretion

SGLT

GLUT

OAT

OCT

Basolateral membrane
Transport systems in the kidney epithelial LLC-PK1 cell line. The
transporters that were assayed for transcellular transport of [18F]FDG
included the sodium-dependent glucose transporter (SGLT), thesodium-independent glucose transporter (GLUT), the organic aniontransporter (OAT), and the organic cation transporter (OCT). The whiteand gray circles indicate high and moderate transporter expression
levels, respectively.

system for sugar efflux [15,19] and an apical SGLT-1
system for Na + -glucose entry [15,20–22]. GLUT-1 is the
only GLUT isoform that has been detected in LLC-PK1
cells. In addition to SGLTs and GLUT-1, LLC-PK1 cells
also express other transporters typical of kidney proximal
tubules such as organic anion transporters (OATs) [23]and organic cation transporters (OCTs) [24], on both theapical and basolateral sides of the cell. OATs and OCTs
are believed to be important for kidney function as
they have extremely broad substrate selectivity and theirsubstrates include not only endogenous anions andcations but also several clinically important drugs [25,26].
In clinical studies, elimination of [18F]FDG through theurine interferes with the visualization of both urologic
diseases around the pelvis and abdominal abnormalities. Inan earlier study using rats, phlorizin (PHZ), an SGLT
inhibitor, improved urinary excretion of [18F]FDG [27].
However, as many transporters reside on the apical andbasolateral sides of the proximal tubules, other transporters
besides SGLT may also be associated with transcellulartransport of [18F]FDG in the kidney. The mechanism oftranscellular transport of [18F]FDG in the proximal tubules
has not been fully elucidated. In this study, the transcellular transport of [14C] labeled FDG ([14C]FDG), overtime, was investigated by the proximal tubules using the
LLC-PK1 cell line and [14C]FDG transport was comparedwith that of [14C] labeled GLU ([14C]GLU). The potential
contribution of OATs and OCTs, which are the maintransporters in the proximal tubules, to [14C]FDG transport
was investigated in addition to that of SGLT and GLUT.

Materials and methods
Materials[14C]FDG, [14C]GLU, and D-[3H]mannitol (100 mmol/l,
37 MBq/ml) were obtained from American Radiolabeled

Chemicals Inc. (St Louis, Missouri, USA). PHZ, phloretin(PHT), and probenecid, (which predominantly inhibit
SGLT, GLUT and OAT, respectively) were acquired
from Sigma-Aldrich (Tokyo, Japan). Tetraethylammonium
bromide (which inhibits mainly OCT) was purchasedfrom Nacalai Tesque (Kyoto, Japan). LLC-PK1 cells wereobtained from Dainippon Pharmaceutical Co. (Osaka,
Japan).
Cell culture and monolayer preparation

Cell studies were carried using the modified methods
described by Shikano et al. and Kiyono et al. [28–30].
Briefly, LLC-PK1 cells were maintained by serial passage
in 25 cm2 cell culture flasks. The cells were fed with
Dulbecco’s modified Eagle’s medium (Sigma-Aldrich)
supplemented with L-glutamine (2 mmol/l) and 10% fetal
bovine serum without antibiotics, in an atmosphere of
5.0% CO2/95.0% air at 371C (pH 7.4). The cells were
subcultured every 5 days using 0.02% ethylenediamine
tetraacetic acid solution and 0.05% trypsin. For the
preparation of a cell monolayer on a micropore support,
the cells were seeded at a density of 5  105 cells/cm2 ona polycarbonate membrane filter (growth surface area:
1.12 cm2, membrane pore size: 3 mm) in Transwell cellchambers. The volume of medium inside and outside theTranswell chamber was approximately 0.5 and 1.5 ml,
respectively. The medium was replaced with fresh
medium every 2 days. The cells were used 4–6 days after
harvesting.
Fig. 2[14C]FDG+ D-[3H]mannitolor
14[ C]GLU
Sampling////

Apical side////

Reabsorption

Incubation
medium
LLC-PK1 cell

Secretion
Basolateral side

Sampling[14C]FDG+ D-[3H]mannitol
or[14C]GLU

Outline of transport experiments using the LLC-PK1 cell line. LLC-PK1
cells were grown as a monolayer on a permeable support in a Transwellcell chamber. [14C] fluoro-2-deoxy-D-glucose ([14C]FDG) or [14C] D-glucose([14C]GLU), together with D-[3H]mannitol, were added to either the
apical or the basolateral side. Aliquots of the incubation medium weretaken from both sides at specified times, and the radioactivity wasmeasured.

Renal transcellular transport of FDG Kobayashi et al. 143

Measurement of transcellular transport using
LLC-PK1 cells

Transcellular transport between LLC-PK1 cells, grownin Transwell chambers, was investigated according to
the scheme illustrated in Fig. 2. Paracellular fluxes
and extracellular trapping of [14C]FDG and [14C]GLU
were calculated using D-[3H]-mannitol, a compoundthat is not transported through the cells. The incubation
medium was Dulbecco’s phosphate-buffered saline[PBS( + ); pH 7.4, adjusted by the addition of HCl or
NaOH solution] containing 137 mmol/l NaCl, 3 mmol/lKCl, 8 mmol/l Na2HPO2, 1 mmol/l CaCl2, and 0.5 mmol/l
MgCl. The Na + -free medium [PBS( – )] used was PBS
in which NaCl and Na2HPO4 were replaced with choline
chloride and K2HPO4, respectively. For transport studies,
the culture medium was removed from both sides of
the cell monolayer and the cell monolayer was firstpreincubated with 0.5 ml PBS( + ) or PBS( – ) on theapical side and with 1.5 ml PBS( + ) or PBS( – ) on thebasolateral side for 10 min at 371C. After preincubation,[14C]FDG (10 kBq; 0.278 mmol/l) or [14C]GLU (10 kBq;
0.250 mmol/l) together with [3H]mannitol were added tothe incubation medium of the apical or the basolateralside. The inhibitors, PHZ, PHT, probenecid, and tetraethylammonium bromide, were also added at a final
concentration of 0.1 mmol/l in PBS( + ) concomitantlywith each tracer addition. For transport measurements,
an aliquot (50 ml) of the incubation medium from the
opposite side of the cell to which the tracer had
been added was obtained at 10, 30, 60, and 90 min after
the start of the tracer incubation, and the radioactivityof each sample was measured. An LSC-51000 liquid

scintillation counter (Aloka) was used to determine the14
C and 3H radioactivity of the collected incubation
media as well as that of the cell monolayer that was
solubilized using 0.5 ml of 1 N NaOH.
Statistical analysis

Measurements are expressed as means ± SD. Statisticalanalyses were performed using an unpaired t-test.
Probability values were 0.01 or 0.05 (P < 0.01, 0.05).

Results
The transcellular transport of [14C]FDG and [14C]GLU,
assessed in Transwell experiments using LLC-PK1 cells, isshown in Fig. 3. Measurements of basolateral-to-apical andapical-to-basolateral transport were carried out in PBS( + )and PBS( – ), and D-[3H]mannitol was assayed to correct forparacellular flux. Transport of both [14C]FDG and [14C]
GLU gradually increased over 90 min after the administration of each radiotracer. The apical-to-basolateral transportof [14C]GLU in PBS( + ) was significantly higher thanthat in PBS( – ) from 30 min of incubation onward. The
transport of [14C]GLU in PBS( + ) was significantly higher
than that of [14C]FDG in either PBS( + ) or PBS( – ) and
was approximately four-fold higher than [14C]FDG at
90 min of incubation. Although the basolateral-to-apicaltransport of [14C]FDG in PBS( + ) or PBS( – ) was not
significantly different from that of [14C]GLU, the basolateral-to-apical transport of [14C]FDG tended to beslightly higher than [14C]GLU at all sampling time points.
The effects of the inhibitors of transcellular transport on
the transport of [14C]FDG and [14C]GLU, in PBS( + ) at
10 min of incubation, are shown in Fig. 4. In the absence

Fig. 3nmol/cm 2

Basolateral-to-apical

Apical-to-basolateral

2.0

2.0

1.5

1.5

1.0

1.0

0.5

0.5

0.0
0

20

40

60

80

0.0
100
0
Time (min)20

40[14C]FDG + PBS(+)[14C]FDG + PBS(−)[14C]GLU + PBS(+)[14C]GLU + PBS(−)

60

80

100

Time-course of transcellular transport of [14C] fluoro-2-deoxy-D-glucose ([14C]FDG) and [14C] D-glucose ([14C]GLU) by LLC-PK1 cells. Transcellulartransport of [14C]FDG (solid line) and [14C]GLU (dashed line) in phosphate-buffered saline (PBS)( + ) (solid symbols) or PBS( – ) (open symbols)
after paracellular flux correction using D-[3H]mannitol is shown. Each point represents the mean ± SD (n = 4 monolayers). wP < 0.01, significant
difference between the sample and the control in PBS( + ) and PBS( – ).

144

Nuclear Medicine Communications 2010, Vol 31 No 2

of inhibitors, the transport of [14C]FDG in either
direction was slightly higher than that of [14C]GLU.
Apical-to-basolateral transport of [14C]FDG decreased
significantly after PHZ treatment compared with thecontrol (P < 0.05) whereas apical-to-basolateral transportof [14C]GLU was significantly lower than the control
after treatment with either PHZ or PHT (P < 0.01,
P < 0.05, respectively). No marked differences in theinhibition of basolateral-to-apical transport were observed
between [14C]FDG and [14C]GLU.

The effects of the inhibitors on the transcellular transportof [14C]FDG and [14C]GLU in PBS( + ) at 90 min of
incubation are shown in Fig. 5. PHT was the only
inhibitor that had any marked effect on the transport of[14C]FDG. However, apical-to-basolateral transport of[14C]GLU was decreased significantly compared withthe control after treatment with either PHZ or PHT(P < 0.01 for both inhibitors). PHT significantly increased the transcellular transport of both [14C]FDG
and [14C]GLU in the basolateral-to-apical direction

Fig. 4

Apical-to-basolateral (nmol/cm2)

Basolateral-to-apical (nmol/cm2)
0.3

0.2

0.1

0.0

0.0

0.1

0.2

0.3

Control
∗

PHZ
PHT

∗

PBC
TEA
[14C]FDG[14C]GLU

Transcellular transport of [14C] fluoro-2-deoxy-D-glucose ([14C]FDG) and [14C] D-glucose ([14C]GLU) after treatment with the indicated inhibitors or
a control. In the figure, the transport of [14C]FDG and [14C]GLU were shown using black bars and white bars, respectively. Inhibitors used were:Phlorizin (PHZ), phloretin (PHT), probenecid (PBC) and tetraethylammonium bromide (TEA) that predominantly inhibit sodium-dependent glucose
transporters (SGLTs), sodium-independent glucose transporters (GLUTs), organic anion transporters (OATs) and organic cation transporters(OCTs), respectively. Transport was assessed at 10 min of incubation in phosphate-buffered saline (+) with or without each inhibitor and paracellular
flux was corrected for using D-[3H]mannitol. Each point represents the mean ± SD (n = 4 monolayers). wP < 0.01 and *P < 0.05, significant
differences between control and inhibitor for [14C]FDG or [14C]GLU transcellular transport.

Fig. 5Basolateral-to-apical (nmol/cm2)
2.0

1.5

1.0

0.5

Apical-to-basolateral (nmol/cm2)
0.0

0.0

0.5

1.0

1.5

2.0

Control
PHZ
∗

∗

PHT
PBC
TEA
[14C]FDG[14C]GLU

Effect of transport inhibitors on transcellular transport of [14C] fluoro-2-deoxy-D-glucose ([14C]FDG) and [14C] D-glucose ([14C]GLU) by LLC-PK1
cells at 90 min of incubation. The effect of transporter inhibitors on the transcellular transport of [14C]FDG (black bars) and [14C]GLU (white bars)
was assayed as described in the legend to Fig. 4, except that the incubation time was for 90 min. PBC, probenecid; PHT, phloretin; PHZ, phlorizin;
TEA, tetraethylammonium bromide. wP < 0.01 and *P < 0.05, significant differences between control and inhibitor for [14C]FDG or [14C]GLU
transcellular transport.

Renal transcellular transport of FDG Kobayashi et al. 145(P < 0.05). The effect of the inhibitors over 30–90 min of
incubation showed a similar trend to that observed at
90 min of incubation.

Discussion
We have characterized the renal transcellular transport(reabsorption and secretion) of FDG in the kidney
proximal tubules using a well-established in-vitro model,
the LLC-PK1 cell line, as well as inhibitors of specifictransporters and multiple assay time points for comparison with GLU transport. Although there are manytransporters in the renal proximal tubules, to date only
the use of an SGLT inhibitor has been reported toincrease the excretion of [18F]FDG in the urine [31]. Our
study did not include an assay of amino acid transportersthat have been proposed to transport [18F]FDG [32,33].
This study is the first report of the potential oftransporters other than SGLT and amino acid transporters
on [18F]FDG transport and extends the earlier dataobtained with the PHZ inhibitor by including an early(10 min) time point in a detailed time-course study of its
effect on [18F]FDG transport over 90 min. This provides
further finding to an earlier report whose first measurement of the reabsorption of filtered [18F]FDG in theproximal tubules after diuretic or PHZ treatment was
at 0–30 min.
Our data on the PHZ inhibitor at early time points are
consistent with the role of SGLT in [14C]FDG transportsuggested by an earlier rat study. In this study, 49% of[14C]FDG in PBS( + ) was reabsorbed by LLC-PK1 cells at
10 min of incubation. The reabsorption of [14C]FDG was
mediated predominantly by SGLT, whereas [14C]GLU was
reabsorbed through SGLT and GLUT (Fig. 4). Reabsorption of GLU, but not FDG, by GLUT is consistent withearlier reported results that substitution of a hydroxy groupat the second position of GLU with a fluorine atom
modulates its ability to be transported by the glucose
carrier [33]. Therefore, FDG will be transported only by
SGLT and not by GLUT, resulting in substantially greaterurinary excretion of [14C]FDG. In the rat study, 56% of thefiltered [18F]FDG was reabsorbed in the proximal tubules
during the first 30 min of diuretic or PHZ treatment [27].
The amount of [14C]FDG reabsorbed by the LLC-PK1
cells after PHZ treatment was slightly lower than thatreported in the rat study. This lower reabsorption is likely
because of the fact that PHZ treatment of rats influences
not only the kidneys but also the entire body.
This study showed little reabsorption of [14C]FDG over
30–90 min after the administration of the radiotracer,
whereas [14C]GLU levels increased dramatically during
this time by reabsorption through SGLT and GLUT
(Fig. 5). In addition, only the SGLT inhibitor, PHT,
significantly increased the secretion of both [14C]FDG
and [14C]GLU over 30–90 min of incubation (P < 0.05).
As we observed a remarkable reduction in the cellularaccumulation of both radiotracers at the basolateral
membrane over this time period (data not shown), theobserved effect of PHT might be influenced by theleakage of the accumulated radiotracer to the apical sideof the proximal tubules because of the inhibition of PHT
GLUT. The other kidney transporters, OAT and OCT,
showed little association with the transcellular transportof [14C]FDG and [14C]GLU. This could potentially bebecause of a lower specificity of these transporters for
FDG and GLU. On account of the described effects of
PHT, FDG was reabsorbed through SGLT at early time
points after the administration of PHT, whereas GLU
was reabsorbed through SGLT and GLUT over the entire
incubation time after the administration of PHT administration. Although neither tracer showed high secretion
mediated by a specific transporter, the secretion of FDG
was higher than that of GLU.
Our data are important for the clinical use of [18F]FDG.
Currently, the clinical use of [18F]FDG-PET is an unsatisfactory method for the detection of malignant neoplasms
around urinary organs because the radioactivity excreted
into the urine hampers interpretation of the PET images.
If SGLT is inhibited at an early phase after the administration of [18F]FDG in a clinical study, kidney reabsorption
could be decreased and urinary excretion promoted. Thiseffect has been shown in an earlier rat study [25]. That is,
GLUT mainly mediates the uptake of [18F]FDG into
the tumor, as well as the excretion of [18F]FDG from thetumor, whereas SGLT predominantly mediates kidney
reabsorption of [14C]FDG. In addition, if GLUT is
inhibited in the delayed phase after [18F]FDG administration in a clinical study, the secretion of [18F]FDG may
be increased. Our data suggest that inhibitors of GLUT
will have little or no influence on tumor accumulationof [18F]FDG at the delayed phase after the administration of [18F]FDG and may also provide a decrease in
the background level of [18F]FDG in the body. However,it should be noted that there are species differences
between pig and human kidney and our findings need tobe confirmed in a human system. Nevertheless, this study
may have important implications for the improvementof the image quality around urinary organs and for the
reduction of radiation exposure in clinical [18F]FDG-PET
studies.

Conclusion
The transcellular transport of [14C]FDG, over time, by
LLC-PK1 cells was clarified and differences in the polarized distribution of transcellular transport between [14C]
FDG and [14C]GLU were shown. Thus, less reabsorptionof [14C]FDG than [14C]GLU, in PBS( + ), was observedin the proximal tubular cells. Reabsorption of [14C]FDG
was mediated mainly by SGLT at early incubation time
points, whereas marked reabsorption of [14C]GLU was
mediated mainly by SGLT and GLUT. The secretionof [14C]FDG also tended to be slightly higher than that

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of [14C]GLU at all sampling times. The PHT inhibitor
significantly elevated the secretion of [14C]FDG and[14C] GLU in the proximal tubular cells over 30–90 minof incubation.

15

16

Acknowledgements

17

The authors thank the staff of the Biological Imaging
Research Center, University of Fukui for their technicalassistance. This study was partly funded by a Grant-in-Aid
for Scientific Research from the Japan Society for the Promotion of Science (17209040, 19790861, and 20249055)
and by the 21st century COE Program (Medical Science).

18

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