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*
Department of Pathology, University of Michigan, Ann Arbor,
Michigan
National Institutes of Health, National Institute of Diabetes and
Digestive and Kidney Diseases, Bethesda, Maryland.
Correspondence to Dr. Lois J. Arend, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, NY 14642. Phone: 716-273-4062; Fax: 716-756-4468; E-mail: lois_arend{at}urmc.rochester.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and
ß subunits, that are important in cell—cell and
cell—extracellular matrix interactions
(1,2).
Integrins have important roles in growth and differentiation
(3,4,5)
and influence various steps in the development of many organs. In the kidney,
several integrins have been shown to be involved in metanephric
differentiation. Mice with a mutation in the gene for the 8
integrin have defects in metanephric differentiation with reduced ureteric bud
branching and defective epithelialization of mesenchyme cells
(6). Mutation of the
3 subunit, which associates with the ß1
subunit, results in reduced branching of the ureteric bud and alterations in
the architecture of developing nephrons
(3). The v
integrin subunit has also been shown to be important in the development of the
metanephros in culture (7).
A unique epithelial integrin subtype, the ß6 integrin
subunit, has been shown to be expressed in the primate kidney, with greater
expression during development than in the adult
(8). The ß6
integrin, which is known to combine with the v subunit to
form a receptor for fibronectin and tenascin
(9,10,11),
may represent a differentiation marker for the nephron, because this protein
begins to be expressed during development of the kidney and declines in
expression as the kidney matures
(8,12).
Expression of ß6 integrin is also increased during periods of
inflammation or repair in the kidney, such as in chronic pyelonephritis or
transplant rejection (8).
ß6 integrin has been shown to be important in regulating the
inflammatory response; a knockout model produced mice with significant
inflammatory infiltration of their skin and lungs
(13). No significant renal
abnormality was noted. The sequence of human ß6 integrin is
known; however, study of kidney development is best performed in the rat or
mouse, where isolation and culture of the metanephros is easily accomplished
and where there is a large database of information on kidney development.
The studies described here deduced the cDNA sequence of the mouse homologue of ß6 integrin and examined the expression of ß6 integrin in the developing and adult mouse kidney. The nucleotide and putative peptide sequences show high homology to human. The expression of ß6 integrin in the mouse kidney differs from that in the human; although expression is greater in the developing kidney than in the adult, expression of ß6 integrin in the mouse nephron is much more ubiquitous. In primate tissue, ß6 integrin expression is described as specifically in macula densa (8,12), whereas in the mouse, expression in the macula densa is not identified until the glomerulus is mature. Expression is also found in proximal convoluted tubule (PCT), the loop of Henle, and collecting ducts. Incubation of mouse metanephric kidneys in culture with antisense oligonucleotides against ß6 integrin resulted in dramatic inhibition of branching of the ureteric bud and differentiation of the mesenchyme. These results demonstrate that in the cultured metanephric kidney, ß6 integrin expression is necessary for normal renal development.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Microdissection of Tubules and Glomeruli
Experiments were performed in Sprague-Dawley rats that weighed 175 to 200
g. The rats were anesthetized by intraperitoneal injection of pentobarbital.
The left kidney was perfused from the aorta, which was cannulated below the
level of the kidneys and ligated proximal to the origin of the left renal
artery. After the renal vein was severed, the kidney was perfused with 30 ml
of cold saline, followed by perfusion with 30 ml of cold DMEM containing 1
mg/ml collagenase. The kidney was removed, cut into coronal slices, and
incubated in DMEM/collagenase at 37°C for 22 min. Slices were rinsed with
cold PBS, placed into DMEM containing 1% fetal calf serum, and maintained at
4°C during dissection. Glomeruli were dissected without tubule or vessel
attachments. In general, 5 to 20 glomeruli or 5 to 10 mm of tubule length were
pooled to constitute one sample. Samples were transferred in 10 µl
dissection medium into 100 µl GITC buffer, snap frozen in liquid nitrogen,
and stored at -80°C for later RNA extraction and cDNA synthesis.
Determination of mRNA Expression by Reverse Transcription-PCR
To determine ß6 integrin expression in microdissected
nephron segments or metanephric kidneys, we snap-froze tissues in guanidine
isothiocyanate solution and stored them at -80°C until use. Total RNA was
then isolated using a discontinuous gradient of cesium chloride, with
Escherichia coli ribosomal RNA as carrier. For RNA isolation from
adult mouse or rat kidneys, pieces of cortex, outer, and inner medulla were
snap-frozen in TRI reagent (Molecular Research Center, Inc., Cincinnati, OH)
and mRNA was isolated according to the manufacturer's directions. cDNA was
synthesized by incubating mRNA at 42°C for 1 h with Maloney murine
leukemia virus reverse transcriptase (Superscript; Life Technologies, Inc.,
Gaithersburg, MD), oligo dT (Pharmacia, Piscataway, NJ) as primer, RNAsin
(Promega, Madison, WI), dithiothreitol, dNTP (Pharmacia), and bovine serum
albumin (Boehringer Mannheim, Indianapolis, IN). The cDNA was precipitated
with linear acrylamide as carrier and resuspended in
Tris-ethylenediaminetetraacetate (TE) buffer.
For amplification, PCR reactions were performed in a total volume of 50 µl in the presence of 0.1 mM dNTP, 10 mM dithiothreitol, 50 mM KCl, 1.5 mM MgCl2, 10 mM Tris (pH 8.3), and 0.001% gelatin, with 0.5 pmol of each primer, 1.25 U Taq DNA Polymerase (Perkin-Elmer Cetus, Norwalk, CT), 1.5 µCi32P dCTP (Amersham, Arlington Heights, IL), and 1 to 2 µl of tissue cDNA. Mineral oil was layered on top of each sample to prevent evaporation. After an initial denaturation at 94°C for 3.5 min, PCR amplification was performed for 30 cycles at 94°C (denaturation) for 1 min, 54°C (annealing) for 1.5 min, and 72°C (extension) for 1 min, followed by incubation at 72°C for 8 min. To ensure that similar amounts of cDNA template were present between the various samples, we performed semiquantitative PCR on ß-actin-normalized cDNA. ß-actin primers were chosen from the coding region of the human ß-actin sequence (15). From each PCR reaction, the product contained in 45 µl was precipitated with 5% linear acrylamide, 4 M ammonium acetate, and 100% ethanol, resuspended in TE buffer (pH 8.0), and run on a 5% polyacrylamide gel. For ß actin, 10 µl of PCR product was directly loaded onto the polyacrylamide gel. 32P incorporation into bands was detected by autoradiography and quantitated using Phosphor Analyst software on a GS-250 Molecular Imager system (Bio-Rad, Hercules, CA).
Cloning of Mouse ß6 Integrin PCR Products
Briefly, PCR amplification products derived from either mouse or rat cDNA
were ligated into the pCR vector (Invitrogen Corp., San Diego, CA), and
competent bacteria were transformed with the plasmid. Positive colonies were
picked and grown in LB media containing ampicillin. Miniprep DNA (Qiagen,
Santa Clarita, CA) from over-night cultures of the clones was sequenced on an
ABI 373A autosequencer. Sequences were compared with known sequences by the
Blast program of the National Center for Biotechnology Information.
Primer Selection
Initial primers were based on the published human sequence (nt 697 to 880;
sense 1, 5' CCG GCT GGC CAA AGA GAT GT; antisense 1, 5' AGT TAA
TGG CAA AAT GTG CT (16). The
resulting 183-bp product was used to screen a 
gt11 oligo dT-primed
library (Clontech Laboratories, Inc., San Diego, CA) from E17 whole mouse.
Partial sequence from the 1800-bp insert obtained from screening the
phage library led to development of new primers that were used for the primary
screening of LambdaZap II libraries as described below.
Library Screening/Plaque Hybridization
Initial screening of a gt11 phage library from E17 mouse with the
183-bp probe produced one positive plaque. PCR of the plaque DNA using
forward primer with ß6 antisense primer and
reverse primer with ß6 sense primer resulted in two products,
800 and 900 bp, respectively. These products were cloned into pCR II, and a
partial sequence was obtained. Primers were designed on the basis of this
sequence for screening LambdaZap II phagemid libraries (Stratagene, La Jolla,
CA) and were as follows: sense 2, 5' AAT AAG CCT CTC AGC GTG GG;
antisense 2, 5' AAT TTC GTT GAA CCT CTG GGC ATC; sense 3, 5'GGA
CCT CTC CGC CTC CAT GG; antisense 3, 5'ATC CCC CAG CCC CAG AGG CT. The
E17 mouse kidney libraries were produced by either oligo dT (designated
library A) or random priming (library B). XL1-Blue-MRF' bacteria were
incubated with phage (50,000 pfu/plate) at 37°C for 15 min then mixed with
top agar, poured onto NZY plates containing ampicillin, and grown for 6 to 8
h. Nylon membranes (Hybond-N, Amersham) were overlaid on each plate,
denatured, neutralized, and rinsed in 2X SSC. The bound phage DNA was
cross-linked to the filter. The filters were prehybridized in Rapid-Hyb buffer
(Amersham) for 30 min at 65°C and hybridized at 65°C with a
random-primed 32P-labeled probe (1 x 106 cpm/ml).
The filters were washed two times in 2XSSC, 0.1% sodium dodecyl sulfate (SDS)
and three times in 0.2XSSC, 0.1% SDS at 65°C. Signal was detected by
autoradiography. Positive clones were identified by presence of signal on
replicate filters. Positive plaques were placed in SM buffer, titered, and
rescreened. In vivo excision was used to obtain positive fragments
from the LambdaZap II vector by using ExAssist helper phage and the SOLR
strain of cells (Stratagene, La Jolla, CA) generating subclones in the
pBluescript SK(-) phagemid. Plasmid DNA was sequenced as described above.
Northern Analysis
Total RNA was isolated from homogenized adult mouse (CD-1) kidney using
TriZol reagent (Life Technologies), and poly(A)+ RNA was then
prepared using the PolyATract mRNA Isolation System (Promega). RNA was run on
a formaldehyde-containing agarose gel and transferred onto a nylon membrane
for subsequent hybridization with a random-primed 32P-labeled probe
(908 bp; primer pair, S3 and AS3). Filters were washed with 0.1X SSC/0.1% SDS
at 60°C. Autoradiography was performed to detect hybridized signal.
In Situ Hybridization and Lectin Histochemistry
For in situ hybridization, both antisense and sense probes were
prepared. A plasmid vector containing mouse ß6 integrin
sequence (nucleotides 601 to 1508) was used as a template for PCR reactions
using primers designed to produce amplification products for the specific RNA
polymerase enzyme to be used and either sense or antisense mouse
ß6 integrin sequence, without extraneous plasmid sequence. PCR
reactions contained either ß6 integrin sense primers, which
included primer sequence for T3 polymerase at the 5' end in combination
with ß6 integrin-specific antisense primers, or
ß6 integrin antisense primers, which included primer sequence
for T7 polymerase at the 5' end in combination with ß6
integrin-specific sense primers. The cDNA produced was used as a template for
in vitro transcription of cRNA probes. Probes were synthesized with
the appropriate T7 or T3 RNA polymerase in the presence of digoxigenin-UTP
(DIG RNA labeling mix, Boehringer-Mannheim Biochemicals) and purified with
NucTrap columns (Stratagene). The probe was precipitated in the presence of
glycogen as carrier and resuspended in the presence of RNase inhibitor.
Relative probe concentration was determined by serial dilutions of the probe,
followed by dot-blotting the diluted probe on nylon membranes and incubation
of the membrane with alkaline-phosphatase—tagged antidigoxigenin
antibody. Detection of signal was by incubation with nitroblue tetrazolium and
5-bromo-4-chloro-3-indolyl phosphate (BCIP). Verification of probe target was
performed by dotting 200 ng of appropriate plasmid DNA on a nylon membrane,
hybridizing with the riboprobe, and detecting the signal as described for
titration of probes. Probes were considered of sufficient concentration if the
signal was detected with 10 to 100 pg of probe. Cryosections of whole mouse
embryos, embryonic kidneys, or perfused newborn or adult mouse kidneys,
mounted on polylysine-treated Probe-On Plus slides (Fisher Scientific,
Pittsburgh, PA), were used for in situ hybridization. Hybridization
was performed for 16 to 18 h at 65°C. Slides were treated with RNase A to
remove nonhybridized probe, and posthybridization washes were performed as
follows: 2X SSC at room temperature (RT) for 15 min, 1X SSC at RT for 15 min,
0.5X SSC at 65°C for 60 min, and 0.5X SSC at RT for 15 min. After
posthybridization washes, sections were incubated with alkaline
phosphatase-conjugated antidigoxigenin antibody (Boehringer Mannheim
Biochemicals) and color was developed with nitroblue tetrazolium and BCIP.
After optimal color development, coverslips were removed and slides were
incubated in TE buffer (pH 7.5) for 5 min. The sections were counterstained
with 0.5% methyl green (Siugma Chemical Co., St. Louis, MO), washed in
dH2O, dehydrated in graded ethanol, and mounted with Permount
(Fisher).
To perform lectin peroxidase co-staining, we performed in situ hybridization on sections as described above, through the point of color development. Slides were then washed in TE buffer and incubated with peroxidase-conjugated lectins (50 µg/ml) in PBS containing Ca2+ and Mg2+ at room temperature for 30 min. Slides were washed three times for 10 min each in PBS without Ca2+ and Mg2+. Diaminobenzidine was used as substrate (Vector Laboratories, Burlingame, CA). Slides were incubated in substrate solution until color developed (2 to 5 min). Slides were then washed in PBS, counter-stained, dehydrated, and coverslipped.
Antisense Oligonucleotide Experiments
Mouse metanephric kidneys isolated at E11.5 were cultured in the presence
of phosphorothioated antisense oligonucleotides (AS ODN) to ß6
integrin (n = 13), v integrin (n = 10), a
nonsense oligonucleotide (NS ODN, n = 10), or Hanks' balanced salt
solution (HBSS) as vehicle control (n = 9). Sequences used were as
follows: ß6 integrin antisense, 5' TCT CGC CAG CTC CAG
ACA GGT GGG TGA AAT T; v integrin antisense, 5' GGA
CCC GCA TAC TCG GCG GGA CTT TCG ACG TCC AGG TTG AAG G; nonsense, 5' TAA
TGA TAG TAA TGA TAG TAA TGA TAG TAA T. The region of the ß6
integrin sequence used for the antisense oligonucleotide sequence was chosen
on the basis of its very low homology to other ß integrin molecules,
particularly ß1 integrin, which is ubiquitously expressed
throughout the kidney. The region was also chosen to be near the 5' end
of the molecule to interrupt mRNA processing as much as possible. The
v AS ODN sequence was used previously by Wada et
al. (7) and was shown to
inhibit growth and differentiation of cultured mouse E13 metanephric kidneys.
The NS ODN was also used in the previous study and was shown to have no effect
on the development of metanephric kidneys in culture. Oligonucleotides were
added to a final concentration of 1.0 µM. Photomicrographs were obtained at
6 d of culture. Kidneys were detached from the filters and placed in TRI
reagent for mRNA isolation and reverse transcription-PCR (RT-PCR) as
described.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Northern Analysis of Adult Mouse Kidney mRNA
The mouse ß6 integrin transcript is approximately 4.5 to
4.8 Kb as determined from Northern analysis of adult mouse mRNA
(Figure 4). The human
ß6 integrin mRNA transcript is reported to be approximately 5
Kb (16).
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Expression of ß6 Integrin mRNA in the Developing and
Adult Mouse Kidney and In Microdissected Rat Nephron Segments by RT-PCR
ß6 integrin mRNA expression is present at 11.5 d of
gestation (E11), which is the initial point of metanephric kidney formation in
the mouse (Figure 5A). The
expression remains low at 14 d of gestation (E14) but is increased at 17 d of
gestation (E17) and again shortly after birth (PND4 and PND7). Expression
declines as the kidney matures (AD). Filter culture of metanephric kidneys
provides a reasonable model system for the study of ß6
integrin in the developing mouse kidney as expression was increased in
cultured explants and peaked after approximately 5 d
(Figure 5B), a time point when
the morphology of the cultured kidneys is similar to that seen in late
gestation and the early postnatal period. Adult rat and mouse kidneys showed
the same overall pattern of expression: approximately equal cortical and
medullary ß6 integrin mRNA expression (data not shown).
Microdissected nephron segments from adult rat kidney
(Figure 6) demonstrated
ß6 integrin mRNA expression predominantly in PCT, in medullary
thick ascending limb and medullary and cortical collecting duct segments, and
to a lesser degree in macula densa—containing segments.
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Expression of ß6 Integrin mRNA in the Developing
Mouse Kidney by In Situ Hybridization and Colocalization with Lectins
Figures 7 and
8 demonstrate expression of
ß6 integrin mRNA in E17 mouse kidneys. ß6
integrin is highly expressed in the developing PCT and loop of Henle (H). The
expression overlaps with that of the lectin Lotus tetragonolobus
(Figure 8, C and D), which
recognizes cells of the PCT in embryonic mouse kidney
(19). Expression of
ß6 integrin is also found in other developing tubule segments,
including the distal convoluted tubule (DCT;
Figure 7F). In developing
macula densa segments, there is no expression of ß6 integrin
mRNA (comma- and s-shaped body stages;
Figure 7, C and D). In
occasional glomeruli, which are more mature (G), a faint juxtaglomerular
signal can be identified. This pattern of expression differs from that
reported in primate kidneys
(16), which was described
specifically as macula densa expression, with little expression elsewhere.
Figure 8 demonstrates that
there is no expression of ß6 integrin in the collecting ducts
at 17 d of gestation, as evidenced by a lack of overlap of the in situ signal
with the signal for the lectin Dolichos biflorus
(Figure 8, A and B).
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Effect of Antisense Oligonucleotides on Metanephric Kidney
Development
Mouse E11.5 kidneys cultured in the presence of a nonsense oligonucleotide
(Figure 9B) or HBSS as vehicle
control (Figure 9A)
demonstrated normal branching of the ureteric bud with development of comma-
and s-shaped bodies by 6 d in culture. As shown previously by Wada et
al. (7), incubation with
an antisense oligonucleotide to the v subunit
(Figure 9C) resulted in
disruption of normal ureteric bud branching and nephron formation. Similarly,
incubation with an antisense oligonucleotide to ß6 integrin
(Figure 9D) inhibited branching
of the ureteric bud, condensation of the mesenchyme, and conversion of
mesenchyme cells to epithelial cells. RT-PCR studies
(Figure 10) demonstrated a
highly reduced expression of ß6 integrin mRNA in kidneys
cultured in the presence of the ß6 integrin ODN but not in the
presence of the nonsense or v antisense
oligonucleotides.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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v
integrin, a promiscuous integrin that associates with several ß subunits,
including ß1, ß3, ß5,
ß6, and ß8. Wada et al.
(7) showed that antibodies to
the v subunit or antisense oligos result in abnormal
nephrogenesis when applied to cultured metanephric kidneys. Studies by
Kreidberg et al. (3)
suggest a role for the 3ß1 integrin in
kidney development as well. Mice that are heterozygous for mutation of the
3 integrin gene demonstrate abnormal branching morphogenesis
and poor glomerular basement membrane formation.
The ß6 integrin, which associates solely with the
v subunit to form a fibronectin and tenascin receptor
(9,10,11),
was described previously to be expressed very specifically in the macula densa
of primate kidneys and to show greater expression during gestation than in the
mature kidney, suggesting a role in the development of the kidney,
particularly the macula densa. Later studies demonstrated enhanced expression
of this subunit in the kidney during inflammation, such as in chronic
rejection, and in other tissues after injury, suggesting a role for
ß6 integrin in inflammation and repair
(8).
Despite the relative lack of expression in the macula densa of the mouse,
ß6 integrin is expressed in high levels in several other
segments of the nephron. The expression of ß6 integrin in the
loop of Henle during development may suggest that this integrin subunit plays
a role in proper development of the loop structure of the nephron. This is
supported by the findings that antisense oligonucleotides to
ß6 integrin severely disrupt the normal development of the
metanephric kidney. The ureteric bud did not branch and there was no
condensation of the mesenchyme around the tips of the ureteric bud.
Subsequently, there was no formation of comma- and S-shaped bodies. A nonsense
oligonucleotide had no effect, whereas an antisense oligonucleotide to
v integrin, which was shown previously to interfere with
metanephric development (7),
produced similar results to the ß6 integrin antisense
oligonucleotide. The results achieved in the present experiments with the
v integrin antisense oligonucleotide were more dramatic than
had been published by Wada et al.
(7), most likely because of the
difference in gestational age at time of isolation of the kidneys. The
previous study isolated the kidneys at E13, when some ureteric bud branching
and nephron development has already occurred. In the present study, the
kidneys were isolated at E11.5, a time point when the ureteric bud has just
entered the mesenchyme. The dramatic effect of the ß6 integrin
antisense oligonucleotide demonstrates the importance of this molecule in the
epithelial—mesenchymal interaction during normal development of the
mouse metanephric kidney. How these findings relate to the lack of a kidney
phenotype in the ß6 integrin knockout mouse
(13) is unclear. However, as
suggested by Sariola (22), the
kidney likely has redundant mechanisms for many important molecules, and
because the v subunit has several ß subunit binding
partners and many of these, including the uniquitous ß1
integrin, are expressed in the kidney, the loss of ß6 integrin
in the knockout may be made up by association of v with one
of its other binding partners. Because the in vitro metanephric
kidney culture does not fully recapitulate the environment of the whole
embryo, these same compensatory mechanisms may not be available in the tissue
culture setting. Recruitment of redundant molecules likely requires input from
surrounding tissues and cells, neurologic input, and the vasculature, all of
which are absent in the tissue culture system.
The results from the present study differ from the original report in primate tissues, which described highly localized ß6 integrin expression in the macula densa (12), particularly in the developing kidney, with no expression in other segments except when there is inflammation in the kidney (8). In the mouse and rat, ß6 integrin is expressed in many nephron segments in both the embryonic and the mature kidney. There is expression mainly in the PCT, thick ascending limb of Henle, and the outer medullary and cortical collecting ducts. There is expression in the macula densa after the glomerulus becomes mature. The discrepancies between our results and the previous study may be due to species differences. Given this difference in ß6 integrin expression between primate and rodent tissues, the full nucleotide sequence of the coding region described in the present study should provide useful information for investigators who study integrins and the extracellular matrix in rodent tissue. This is particularly relevant for investigators in the field of kidney development, where many of the previous studies were and current research is performed with rat or mouse tissue.
In summary, this study demonstrates that mouse ß6 integrin is similar to the primate molecule; it is expressed in the developing and mature mouse kidney, and in the cultured metanephric kidney setting the lack of ß6 integrin expression has dramatic effects on renal development.
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Acknowledgments |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5 integrin-deficient mice.
Development 119:1093
-1105, 1993[Abstract]
4 integrins are essential in placental and cardiac
development. Development. 121:549
-560, 1995[Abstract]
8ß1 is
critically important for epithelial-mesenchymal interactions during kidney
morphogenesis. Cell 88:603
-613, 1997[Medline]
v cDNA and role of the
v-related matrix receptors in metanephric development.
J Cell Biol 132:1161
-1176, 1996vß6 in cell
attachment to fibronectin: Heterologous expression of intact and secreted
forms of the receptor. J Biol Chem269
: 6940-6948,1994This article has been cited by other articles:
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