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0 1996
Endocrmology
and Metabolism
by The Endocrine
Society
Cell-Specific
Localization
Proteins
in Mammalian
SHERIN
U. DEVASKAR
AND
DAPHNE
of Glucose
Lung*
E.
Transporter
DEMELLO
Division of Neonatology
and Developmental
Biology, Department
of Pediatrics,
University of
Pittsburgh,
Magee Womens Research Institute
(S.U.D.), Pittsburgh,
Pennsylvania
15213; and the
Department
of Pathology, St. Louis University School of Medicine,
Pediatric
Research Institute,
Cardinal
Glennon Children’s
Hospital (D.E.d.), St. Louis, Missouri
63110
ABSTRACT
Mammalian
lung uses glucose
for cellular
oxidative
metabolism,
growth,
differentiation,
surfactant
synthesis,
and host defense.
Intracellular
transport
of glucose is accomplished
by membrane-associated glycoproteins
termed
glucose
transporters
(Gluts).
To determine the cell-specific
localization
patterns,
human
autopsy
lung
tissue from preterm
(24-32
weeks; n = 41, term infants (38-40
weeks;
n = 4), and adults (n = 4) was analyzed
for facilitative
Glut isoforms
and the energy-dependent
sodium-glucose
cotransporters
(SGLT)
by
Western
blot analysis and immunohistochemistry.
Antibodies
specific
for human
Glut-l
(erythrocyte,
blood-brain
barrier
type),
Glut-3
(brain),
Glut-4
(insulin-responsive
skeletal
muscle/adipocyte),
and
Glut-5
(kidney/jejunum)
were employed.
Analysis
of Glut-2
(liver/
pancreatic
P-cell/small
intestine)
was performed
in newborn
and
adult rat lungs, and analysis
of SGLTl
(kidney/small
intestine)
was
conducted
in newborn
and adult rabbit
lungs, because of the species
specificity
of the antirat
Glut-2
and antirabbit
SGLTl
antibodies
employed.
In human
lung at all ages, our studies
revealed
an ap-
C
ELLULAR
oxidative
metabolism
is a vital process for
the maintenance
of biological
function.
Meeting
the
energy requirements
for oxidative
metabolism
in many tissues is dependent
on a sustained supply of glucose (1). The
lung, a vital organ that performs the function of oxygenation
and defense against a host of factors, uses glucose for cellular
oxidation
(2), growth, development
(3), and biological
functions such as surfactant synthesis and secretion (4). Glucose
is transported
intracellularly
by a family of closely related,
heterogeneously
glycosylated
membrane-spanning
proteins
termed the glucose transporters
(Gluts) (5,6). To date, limited
studies involving
the characterization
of Gluts in lung exist.
Although
lung glucose transport
in vitro has been determined to be via sodium-dependent
(7,8) and independent
(9)
mechanisms,
the ubiquitous
facilitative Glut isoform (Glut-l)
alone has been observed in situ (10) and in cultured rat lung
cells (11, 12). In addition
to transporting
glucose, this particular isoform has been observed to transport water (13) and
ascorbic acid (14); both of these properties
are essential for
proximately
45- to 50-kDa
Glut-l
protein
band in entrapped
erythrocytes and perineural
sheaths, which serve as a blood-nerve
barrier.
In the rat lung, an approximately
45-kDa
Glut-2 band was seen in the
rat bronchial
columnar
epithelium.
Glut-3
was observed
in term infant and adult white blood cells and neuroendocrine
cells, representing neuronal
elements
of the autonomic
nervous
system.
Glut-4,
Glut-5,
and SGLTl
were not detected
in lung. We conclude that Gluts
are expressed
in nonalveolar
lung cell types arising
from stem cells
of the erythroid
cell lineage
and tissue barrier
epithelia
(Glut-l),
foregut
epithelium
(Glut-21,
myeloid
cell lineage
(Glut-31,
and neuroectoderm
(Glut-3).
No detectable
levels of Glut-4,
Glut-5,
or SGLTl
Gluts were noted in mammalian
lung. The absence of a Glut isoform
in the alveolar
lining
epithelial
cells suggests
minimal
expression
of
the Glut isoform
or the presence
of some other transport
system,
reliance
on adjacent
cells for substrate
supply,
or uptake
of nonglucase substrate
to fuel a relatively
low glucose-demanding
cellular
system.
(J Clin Endocrinol
Metab
81: 4373-4378,
1996)
normal lung maturation
(15), pulmonary
fluid balance (16),
and protection
against lung injury (17). To determine
the
transporter
isoform that mediates transport into the different
human lung cells, we undertook
the present study in human
postmortem
lung tissue and attempted
to demonstrate
the
cell-specific
localization
of various Glut isoforms within the
two major families of the facilitative
and sodium-glucose
cotransporters.
When species-specific
reagents precluded
the
study of human
tissue, rat or rabbit lung tissues were
examined.
Materials
and Methods
Tissue preparation
Autopsy
samples of infant (24-32 weeks, n = 4; 38-40 weeks, n = 4)
and adult (n = 4) human lungs, adult frontal cortex, diaphragm,
skeletal
muscle, and kidney
were obtained
within
6-12 h postmortem
and immediately
snap-frozen
in isopentane
and liquid nitrogen
and stored in
air-tight
containers
at ~70 C. The control tissues were obtained
from the
same autopsy
as the lung to which they were being compared.
For tissue
sections, lungs were either fixed by immersion
in 4% paraformaldehyde
at 4 C for 2 h and cryoprotected
in 30% sucrose overnight
at 4 C or
embedded
in paraffin
after formalin
fixation
by immersion
for 12 h.
Newborn
and adult rat and rabbit lungs were preserved
in a similar
manner.
Adult rat liver and adult rabbit intestinal
brush border
membranes were used as positive controls. The experimental
protocols
(principal investigator,
D.E.D.) were reviewed
and approved
by the institutional review
board for human
investigation.
The NIH guidelines,
as
approved
by the institution,
were followed
in the care and use of animals
(principal
investigators,
S.U.D. and R.B.M.).
Received January 30, 1996. Revision
received
July 11, 1996. Accepted
August 20, 1996.
Address
all correspondence
and requests
for reprints
to: Dr. Sherin
l-J. Devaskar,
Department
of Pediatrics,
300 Halket
Street, Pittsburgh,
Pennsylvania
15213-3180.
* Presented
in part at the Annual
Meeting
of the Society for Pediatric
Research, Washington,
D.C., May 1993. This work was supported
by the
American
Diabetes
Association
(to S.U.D.),
NIH Grant HD-25024
(to
S.U.D), and the American
Lung Association
(to D.E.D).
4373
DEVASKAR
AND
DEMELLO
JCE & M . 1996
Volt31 . No 12
-5OkD
iii&
Lung
hiid
Brain
-
w
Human
Lung
Brain
D
..f<
>‘.:.
:.,::.
::I
:.i.,:’
., -45kD
.z,. \\
Humal
Lung
Human
Lung
$iuman
Kidney
Human
Diaphragm
FIG. 1. Western
blot analysis
of Glut-l,
Glut-2,
Glut-3,
Glut-4,
and Glut-5
proteins.
Representative
autoradiographs
of Western
blots demonstrating
a 45kDa
Glut-l
protein
band in 50 or 100 pg human
lung and brain homogenates
(A). A 50-kDa
Glut-3 protein
is seen in 50 or 100
pg human
brain homogenates,
but is absent in 50 or 100 pg human
lung homogenates
(B). An approximately
45kDa
Glut-4
protein
is noted
in 50 or 100 pg human
diaphragmatic
homogenate,
but is absent in either 50 or 100 pg human
lung homogenate
(C). An approximately
47-kDa
Glut-5 protein
band is present
in 100 pg human kidney
homogenate,
but is absent in 100 pg human lung homogenate
(D). Similar
45-kDa
Glut-2
protein
bands are seen in 100 pg adult rat liver (lane 1) and lung (lane 2) homogenates,
but not in the trachea
(lane 3) (E). Glut-2 protein
was
not detected
in 100 pg human
liver and lung homogenates
(negative
data not shown).
Antibodies
The preparation
and characterization
of the antibodies
used have
been described
previously
(18-23).
In all cases the primary
antibodies
were raised in rabbits. The anti-Glut-l,
anti-Glut-3,
and anti-Glut-5
antibodies
were directed
against the corresponding
human
C-terminus
neutides
and tested for isoform
suecificitv
(18, 19, 22). The anti-Glut-4
&&body
was an antirat Glut-4 Ig’G capadle‘of
detecting
human
Glut-4
(21). The anti-Glut-2
antibody
was raised against the rat gluthione-Stransferase
(GST)-Glut-2
fusion protein
(20), and the anti-SGLTl
antibodies were directed
against derived
peptides
of the rabbit SGLTl (23).
Other commercially
available
antihuman
Glut-2
IgGs were also used
without
optimal
detection
or resolution.
To overcome
the potential
of
detecting
closely related sodium-dependent
nucleoside
(24), amino acid
(25), or ion transporters
(26), two separate antirabbit
SGLTl antibodies
were employed.
One (no. 8792) was raised against the extracellular
loop
(402-420
residues),
cytoplasmic
region
Western
and the other (no. 8821) was raised
(604-615
residues)
of the protein
(23).
against
the
blot analysis
Tissue samples (human,
rat, and rabbit) were prepared
and subjected
to Western blot analysis as previously
described
(19,22). Only in the case
of the sodium-glucose
cotransporters
was the chemiluminescence
detection system used as well to enhance
the sensitivity.
The primary
antibodies
used for detection
included
the rabbit antihuman
Glut-l
antibody
at a dilution
of 1:200 (18), the antirat GST Glut-2 at a 1:500
dilution
(20), the antihuman
Glut-3
at a 1:50 dilution
(19), the antirat
Glut-4 at a 1:500 dilution
(21), the antihuman
Glut-5 at a 1:lO dilution
(22), or the two antirabbit
SGLTl antibodies
at a 1:500 dilution
(23). As
the antirat
GST-Glut-2
and the antirabbit
SGLTl
antibodies
failed to
GLUTS IN hMMMALIAN
detect the corresponding
employed,
respectively.
human
proteins,
Immunohistochemical
analysis
rat and rabbit
lungs
were
Immunoperoxidase
staining
was performed
on frozen
or paraffin
sections of lungs as previously
described
(27). The dilutions
in PBS of
the antibodies
for the primary
incubation
step were: Glut-l,
1:250 optimal dilution;
Glut-2,
1:20; Glut-3,
MOO; Glut-e
1:50; Glut-5,
1:lO;
SGLTl 8972, 1:50; and SGLTl 8821, 1:50. The secondary
antibody
was
goat antirabbit
cross-linked
with horseradish
peroxidase.
Preimmune
rabbit serum and the specific
antibody
preabsorbed
with saturating
concentrations
of the corresponding
peptide
were used in the primary
incubation
step as negative
staining
controls.
All sections were counterstained
with fast green.
Results
Western
blot analysis
An approximately 45-kDa Glut-l protein band was noted
in human lung (Fig. 1A) similar to that seenin human brain.
In addition, a larger band of about 60 kDa was found in the
lung, representing differentially glycosylated forms, along
with considerably smaller sized bands. No Glut-3, Glut-4, or
Glut-5 protein was found in human lung tissue, although in
the positive tissue controls, namely human brain (Glut-l and
Glut-3), diaphragm and skeletal muscle (Glut-4), and kidney
(Glut-5), the respective protein bands were detected (Fig. 1,
B, C, and D). Glut-2 was present as a 45-kDa band in rat lung
as well as in the positive control, rat liver (Fig. lE), but not
in rat trachea. The antirat GST-Glut-2 antibody was species
specific and failed to detect Glut-2 in human lung (data not
shown). As the isoform specificity of all of the antifacilitative
Glut antibodies used in this study has been extensively demonstrated previously by us and others using the corresponding Glut peptides (M-23), the peptide competition blots for
each antibody have not been repeated here. Using both antiSGLTl antibodies, a faint approximately 75- to 80-kDa band
was observed in a preparation of intestinal brush border
membranes (Fig. 2, B and D, lane l), and this was absent
when the antibodies were preabsorbed with saturating concentrations (10 pg/mL) of the respective peptides (Fig. 2, A
and C, lane 1). Similar SGLTl protein bands were not seen
in human, rat, or rabbit lung (Fig. 2, B and D, lanes 2-4).
However, an approximately 75-kDa protein band was observed in rat and rabbit kidney (Fig. 2, B and D, lanes 6 and
7); the former was competed by the peptide when 8821 an-
LUNG
tibody was used, and the latter was competed by the peptide
when the 8792 antibody was employed (Fig. 2, A and C, lanes
6 and 7).
Immunohistochemical
FIG. 2. Western
123456
results
Glut-l immunoreactivity at all agesexamined was limited
to human red blood cells and cells constituting the perineural
sheath, which forms the blood-nerve barrier (Fig. 3A). Glut-2,
on the other hand, was observed on the luminal surface of rat
columnar epithelial cells lining the bronchus (Fig. 3D). The
specificity of this Glut-2 immunoreactivity was confirmed by
the absence of positive staining in the presence of a Glut-2
peptide-preabsorbed antirat Glut-2 antibody (Fig. 3E).
Glut-3, although not detected by Western blot analysis, was
noted in white blood cells in term infant and adult human
lungs (Fig. 3C) and in neuroendocrine cells within alveolar
walls (Fig. 3B). Similar Glut-3 immunoreactivity was not
evident in the preterm human lung sections. Neither Glut-4
nor Glut-5 was detected in any human lung sections, although each was successfully immunolocalized in the sarcolemmal membranes of the adult skeletal muscle and in
kidney tubules, respectively. Immunohistochemical studies
employing the two antibodies raised against the rabbit
SGLTl form of the sodium-glucose cotransporters failed to
demonstrate any immunoreactivity in either adult human or
rabbit lung or kidney sections (negative data not shown).
Discussion
The mammalian lung expressesspecific Glut proteins that
belong to the facilitative class. The cell-specific expression
pattern for Glut-l noted in adult lungs was present in neonatal lungs aswell. Glut-l was found in human red cells and
perineural cells. This observation in human lung is similar to
that previously reported in mouse lung (10) and adult rat
skeletal muscle (28). No other cell type, including the alveolar
epithelial cells, expressed Glut-l. This localization pattern of
Glut-l distribution in “barrier” tissue (29) is similar to that
seen in other organs, such as the brain (19, 30), the eye (31),
and the placenta (32). The absenceof Glut-l in lung alveolar
cells is in contrast to the results of studies in vitro, which
demonstrated Glut-l messenger ribonucleic acid (mRNA)
levels and glucose-transporting function (11, 12). This difference perhaps stemsfrom the fact that Glut-l expression is
D.
c.
1234567
4375
7
1234567
1234567
blot analysis
of the SGLTl
protein.
An approximately
75 to 80-kDa
protein
band was detected
with the anti-SGLT18821
(B)
and anti-SGLTl
8792 (D) in 15 pg adult rabbit
intestinal
brush border
membranes
(lane 1). Competitive
inhibition
of this approximately
75
to 80-kDa
SGLTl
protein
band was noted in the presence
of 10 wg of the corresponding
peptides
(A, 8821; C, 8792). No similar
specific SGLTl
protein
band was noted in 100 pg human
(lane 2), rat (lane 3), or rabbit (lane 4) lung. An approximately
75-kDa
band was noted in 100 pg rat
and rabbit
kidney
tissue (lanes 6 and 7), which was displaced
by the 8821 (A) and 8792 (B) peptides,
respectively.
A similar
SGLTl
protein
band was absent in human
kidney
tissue (lane 5).
4376
DEVASKAR
AND DEMELLO
JCE & M
Vol81.
l
1996
No 12
FIG. 3. Immunohistochemical
analysis. Glut-l immunoreactivity
was restricted to the cells of the perineural sheath (short arrow) and red cells
in human lung (long arrows). No other cell in the lung demonstrated Glut-l staining (A). Glut-3 was noted in human neuroendocrine cells found
within the walls of the alveoli (short arrows; B). Additionally, white blood cells (short arrows) demonstrated Glut-3 immunoreactivity (C). Glut-2
immunoreactivity
was noted predominantly in the columnar cells (long arrows)
lining the rat bronchus (D) and appears darker than that in
a peptide-preabsorbed
rat control lung section (E).
induced or enhanced when cells are cultured (3, 33). This
phenomenon was observed in T antigen-immortalized pancreatic p-cells (34) and primary hepatocytes (35) that express
only Glut-2 and in neurons that express only Glut-3 in situ
(18, 36-38).
Glut-2, the high K, transporter, is expressed primarily by
adult hepatocytes, pancreatic p-cells, and the epithelial cells
lining the small intestine (5, 6). Similar to this distribution,
Glut-2 was observed only in the columnar epithelial cells
lining bronchi, but not trachea. As the airways develop asan
GLUTS IN MAMMALIAN
outpouching from the embryonic foregut, it is not surprising
that the airway lining epithelial cells continues to express
Glut-2. Glut-3, which is primarily a neuronal Glut (20, 38),
was localized to cells of neuroendocrine origin. Neither the
perineural sheaths nor the nerve terminal fibers demonstrated any Glut-3 immunoreactivity. In addition, as described previously, Glut-3 was present in white blood cells
(20,39). Of interest was the developmental pattern of Glut-3
expression only in term infant and adult lungs, with no
comparable expression in preterm infant lungs. The fact that
no Glut-3 was noted even in adult lung homogenates using
Western blots relates to the amount of entrapped white blood
cells, which is highly variable, and the low numbers of Glut-3
immunoreactive neuroendocrine cells observed. The insulinresponsive Glut-4 and the fructose transporter Glut-5 (40)
were absent in all lung cell types in both adults and infants.
This absenceof specific isoforms could not be due to the use
of postmortem tissue, as we were able to detect both Glut-l
and Glut-3 in similarly prepared and preserved human tissues,and both Glut-4 and Glut-5 were demonstrated in other
control tissues that were also similarly prepared and preserved. Other facilitative Gluts, such as Glut-6, a pseudogene
that encodes a 11.3-kilobase mRNA (41), and Glut-7, which
is the endoplasmic reticulum/microsomal form of Glut-2
(42), were not examined in this study.
The family of sodium-glucose cotransporters consistsof at
least four isoforms: SGLTl (43,44), SGLT2 (45), Hu14 (46,47),
and rkST1 (48). SGLTl, the major high affinity form examined in our study, shareshomology with the sodium-neutral
amino acid transporter (25), the mammalian sodium nucleoside transporter (24), and the sodium myoinositol cotransporter (49). This SGLTl sodium-glucose cotransporter transports glucose, sodium, water, amino acids, carboxylic acids,
nucleosides, and ions (50). Based on these transport characteristics and the fact that in vitro glucose is transported into
lung cells in a sodium-dependent manner (7, 8), one could
potentially expect the presence of sodium-glucose cotransporters in the alveolar lining epithelial cells, especially type
I cells.
Typically, the SGLTl isoform is expressed by the brush
border of small intestinal lining epithelial cells and by those
cells lining the proximal tubules within the kidney medulla,
the former expressing considerably greater levels than the
latter (51, 52). We detected the approximately 75- to 80-kDa
sodium-glucose cotransporter in the intestinal brush border
membranes by Western blot analysis using antibodies
against the cytoplasmic or extracellular domains of the peptide. In the kidney, the antibody directed against the cytoplasmic domain of SGLTl demonstrated peptide specificity
in detecting the protein in the rat kidney, whereas the antibody raised against the extracellular domain of the SGLTl
protein expressed peptide specificity in the rabbit kidney. In
contrast, no SGLTl protein band was noted in the human, rat,
or rabbit lungs. Recent studies in rats demonstrating minimal
concentrations of SGLTl mRNA in kidney, liver, and lung
(53) support the presence of minimal levels of this sodiumglucose cotransporter in mammalian lung. Whether the detection of SGLTl mRNA represents the true presence of this
isoform in rat lung or cross-hybridization with a closely
homologous mRNA speciesdetected at low stringency con-
4377
LUNG
ditions, as observed with the recently characterized low affinity SGLT2 in other tissues(54), remains to be determined.
Similarly, the capability of detecting exceedingly low levels of the corresponding protein with the two antibodies
employed in this study may be limited. More importantly,
separate studies involving intestinal Na+/glucose cotransporter expression have demonstrated a dissociation between
the mRNA and protein levels in a different tissue (55). The
use of two antibodies, one raised against the 402-420 amino
acid residues of the extracellular loop, and the other to the
604-615 residues of the cytoplasmic domain of the rabbit
SGLTl in immunohistochemical analysis, however, did not
detect SGLTl in any pulmonary cell type of either the human
or rabbit neonatal and adult lung or kidney sections. This
contrasts with our Western blot results and may relate to the
antibody‘s sensitivity in detecting low amounts of the peptide that is present in the kidney (observed on Western blots)
as opposed to the gastrointestinal brush border membranes.
Our present studies do not exclude the presence of other
Nat /glucose cotransporter isoforms in mammalian lung,
although others have reported the absenceof SGLT2 in rat
lung (54).
In conclusion, Glut-l, Glut-2, and Glut-3 are expressed in
mammalian lung, supporting the presence of mechanisms
mediating facilitative glucose transport into this tissue. Although SGLTl, Glut-4, and Glut-5 could not be detected or
localized in a cell-specific manner, Glut-l, Glut-2, and Glut-3
were localized in pulmonary nonalveolar cells. This cellspecific localization pattern of the three facilitative Gluts in
the pulmonary system recapitulated the distribution in other
nonpulmonary tissues. Of significance was the absence of
any of the examined facilitative Glut isoforms in the alveolar
epithelial cells, suggesting cryptic levels of the transporter
protein(s), minimal levels of the SGLTl protein that could not
be immunologically detected, the presenceof someother yet
to be described transport system, reliance on adjacent cells
for substrate supply, or alveolar epithelial uptake of nonglucose substrates to fuel a relatively low glucose-demanding cellular system (11).
Acknowledgments
Antifacilitative
Gluts antibodies
were provided
by D. E. James (Washington University
School of Medicine,
St. Louis, MO), and the sodiumgl;cose
cotransporter
antibodies
were provided
by B. A. Hirayama
and
E. M. Wright
(Universitv
of California,
Los Angeles.
CA). We thank B.
A. Hirayama
and E. M: Wright
for their assisyance with the sodiumglucose cotransporter
studies, S. Kalyanaraman
and Sarah T. Heyman
for their technical
assistance,
and Richard
B. Mink, St. Louis University
(St. Louis, MO), for providing
the adult rabbit tissues.
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