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Centre d’ Investigacions en Bioquímica i Biologia Molecular (M.J.M., N.B., A.M.), Hospital Universitari Vall d’ Hebron, Barcelona 08035, Spain; and Trafford Centre (M.H.), University of Sussex, Falmer, Brighton, Sussex BN1 9RY, United Kingdom
Address all correspondence and requests for reprints to: Anna Meseguer, Centre d’ Investigacions en Bioquímica i Biologia Molecular, Hospital Universitari Vall d’ Hebron, Passeig Vall d’ Hebrón 119–129, 08035 Barcelona, Spain. E-mail: meseguer{at}ar.vhebron.es
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase was decreased. Expression of these transcripts was
inhibited in dihydrotestosterone-treated females by flutamide and in
males by castration, confirming their dependence on androgens. Although
all the genes demonstrate tissue-specific regulation by androgen, SA
showed both kidney specificity and absolute requirement for androgen
for its expression. These newly identified androgen-regulated genes
will constitute very useful models for studying the nature of
tissue-specific gene regulation by androgens. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Androgens, as well as other steroid hormones, vitamin D, and thyroid hormones function in different biological programs through the binding of intracellular receptors, which act as ligand-inducible transcription factors on specific DNA elements of target genes (see Refs. 1 and 2 for reviews). The DNA-binding domain of the androgen receptor displays a remarkable amino acid sequence identity with that of glucocorticoids, progesterone, and mineralocorticoid receptors, and all activate the same hormone-response element, which was originally defined as the consensus response element for glucocorticoids (GGTACAnnnTGTTTCT) (2, 3). The difficulty of understanding how these four different steroids can exert specific actions under physiological conditions has been recently clarified by the demonstration that hormone specificity lies in the ability of nonreceptor factors to distinguish and interact between a set of receptors that recognize a common DNA response element (4, 5). The arrangement of the hormone-response element within the promoter is critical, since the presence of adjacent hormone-responsive elements and their proximity to binding sites for transcription factors may alter the specificity as well as the magnitude of the hormonal response (6, 7, 8, 9).
The murine kidney has been extensively used as a model for androgen
action because, contrary to their effects in the accessory sex organs
of the male reproductive tract, androgens lead only to hypertrophic
changes in kidney, with no increase in DNA replication (10), and
testosterone itself is the primary effector of the androgenic response,
due to low or nonexistent levels of 5--reductase (11). The
inducibility of genes such as those coding for ß-GLUC (12, 13),
ornithine decarboxylase (ODC) (14), alcohol dehydrogenase (ADH) (15),
kidney androgen-regulated protein (KAP) (16) and RP2 (17), classically
used as markers for androgen action in mouse kidney, shows striking
variation among different strains and species of mice (10, 18, 19, 20).
Furthermore, they also show differential sensitivity to androgens upon
androgen stimulation in identical samples (21). Although
glucocorticoid-response element-like sequences have been found in
regulatory regions of all of these genes, detailed characterization of
the molecular elements mediating androgen-responsive gene
expression in the kidney has proved to be difficult. In addition to the
lack of an appropriate androgen-responsive cell culture system for DNA
transfection studies, the current gene models available are, in fact,
quite different in their kinetics of induction, their capability to
respond to other hormonal stimuli (22), and in the involvement of other
hormones in their androgenic response (23, 24). Therefore, attempts to
identify common cis- and trans-elements involved
in androgenic regulation of gene expression in mouse kidney have
failed.
Since androgen hormone action is promoter-, cell-, ligand-, and species-dependent, we have undertaken a project aimed at identifying novel kidney androgen-regulated genes whose expression is controlled by dihydrotestosterone (DHT) under identical induction conditions and in the same mouse strain. We adopted a combined approach, using both the differential display-like technique of random arbitrarily primed PCR (RAP-PCR) (25, 26) and the PCR-coupled subtractive hybridization method of cDNA representational difference analysis (cDNARDA) (27). cDNARDA is an effective and sensitive method that has been successfully applied to a number of different problems, including identification of cell line and tissue-specific gene expression (28); targets of hormone action; and targets of transcription factor action (29, 30) and developmental gene expression (31, 32). RAP-PCR permits the detection of lower degrees of regulation than cDNARDA, and up- and down-regulation can be selected in the same assay. Using this complementary approach, we have been able to demonstrate unique differences in gene expression between mouse kidney samples from sham- and DHT-treated C57BL/6 female mice. The isolation and identification of coordinately up-regulated genes in this system have provided new targets of androgen action that will be extremely useful to further define the elements and delineate the mechanisms underlying the generation of an androgen-regulated phenotype in mouse kidney.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male mice were castrated under droperidol and midazolam anesthesia and allowed to recover for 8 days before receiving further treatment.
DHT- and hormone free-containing implants were obtained from Innovative Research of America (IRA, Sarasota, FL) and used as previously described (33). Androgen-treated animals were treated for a period of 8 days with a DHT dose of 19 µg/day and killed by cervical dislocation. When required, 5 mg of the antiandrogen flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl) phenyl] propanamide) were prepared in 0.4 ml 3:1 (vol/vol) sesame oil/absolute ethanol vehicle and injected sc daily, for a period of 8 days concomitantly with the DHT-containing pellets.
All the experimental animal procedures were conducted in accordance with Institutional standards that fulfil the requirements established by the Spanish Government and the European Community (Real Decreto 223/1988: B.O.E. No. 67, 3/18/88, and B.O.E. No. 256, 10/25/90).
RNA isolation
Total RNA was extracted from kidneys of DHT- and sham-treated
female animals using the guanidinium thiocyanate method (34).
PolyA+ selected RNA was isolated using the messenger RNA
(mRNA) purification kit (Pharmacia Biotech, Inc., Uppsala, Sweden).
Arbitrarily primed PCR of RNA (RAP-PCR)
Total RNA from kidneys of DHT- or sham-treated female mice was
processed as described by Ralph et al. (26) with some
modifications. Briefly, 1 µg deoxyribonuclease-treated RNA was
denatured at 70 C for 10 min and placed on ice before cDNA synthesis.
Oligo(dT) primer (5 µM) was used to initiate first-strand
cDNA synthesis, using Moloney Murine Leukemia Virus (MoMLV) reverse
transcriptase (Promega Corp., Madison, WI), following the protocol
previously reported (26).
Second-strand cDNA was synthesized by arbitrary priming PCR, using the
oligos: aT3A, 5'-TTGGGTGTGGTCTCT-3'; MAYA,
5'-CAGCATTTCTCATCC-3' and 3.99R, 5'-TTCGGGGGCCAGCTA-3'.
Different amounts (3 and 6 µl) of the first-strand synthesis reaction
were mixed with a buffer containing 50 mM KCl, 10
mM Tris, pH 9.0, 0.1% Triton X-100, 1.5 mM
MgCl2, 0.2 mM each deoxynucleoside
triphosphate, 0.1 mCi/ml [33P]dATP,1 U Taq
polymerase (Perkin Elmer-Cetus, Norwalk, CT) and 1 µM of
each of the arbitrarily chosen primers, in a final volume of 25 µl.
The reaction mixtures (one for each arbitrary primer) were subjected to
94 C for 5 min to denature, followed by two low-stringency PCR cycles
(94 C for 5 min, 40 C for 5 min, and 72 C for 5 min) and by 40
high-stringency PCR cycles (94 C for 1 min, 60 C for 1 min, and 72 C
for 2 min), with a final extension of 72 C for 7 min. Two microliters
of each reaction were denatured at 95 C for 5 min, loaded into a 6%
acrylamide-8 M urea sequencing gel, and electrophoresed at
high voltage until the xylene cyanol dye reached the bottom of the gel.
After run, the gel was dried and exposed to Hyperfilm-MP x-ray film
(Amersham, Arlington Heights, IL).
Differentially amplified RAP products were excised from the gel, eluted, and reamplified as previously described (26).
Representational difference analysis of cDNA (cDNARDA)
Double-stranded cDNA was synthesized from 5 µg mRNA from
kidneys of DHT- (tester) or sham-treated female mice (driver) and
cDNARDA was performed as described by Hubank and Schatz (27).
Sequences of the oligonucleotides used to prepare adaptors and for PCR
amplification are the same as those described by Hubank and Schatz
(27).
After two rounds of subtraction and amplification, difference products were run in a 1.3% agarose gel and stained with ethidium bromide to visualize bands. After being excised and eluted from the gel, they were cloned and used as probes in Northern blot analysis.
Preparation of clones
RAP differential bands were cloned into the pGEM vector
(Promega), and RDA differential products were cloned into the
pBluescript II SK+ vector (Stratagene, La Jolla, CA). When
possible, 10 independently isolated colonies were picked for each RAP
and RDA product, and plasmid minipreparations were made using the
Wizard System (Promega). Clones were checked for inserts by PCR or by
restriction digestion: NcoI and PstI enzymes for
RAP products and XbaI and PstI for RDA
differential clones (Boehringer-Mannheim, Mannheim, Germany), followed
by an agarose gel.
Northern blot analysis
Three micrograms of mRNA were electrophoresed in a 6.5%
formaldehyde-1.4% agarose gel, blotted to Hybond N nylon membranes
(Amersham), and hybridized with random priming 32P-labeled
cDNA probes (Stratagene) at 42 C in 50% formamide. After
hybridization, filters were washed four times at room temperature for
10 min in 2x saline sodium citrate/0.1% SDS, followed by 1 h at
50 C in 0.2x saline sodium citrate/0.1% SDS. The
glyceraldehyde-3-phosphate dehydrogenase probe was used as an internal
control on each hybridization.
Sequencing and identification of differential products
Sequence analysis of differentially expressed cDNA products was
effected with the Sequenase version 2.0 DNA sequencing kit (USB Corp.,
Cleveland, OH). Resulting sequences were compared with the GenBank and
dbEST databases using the BLAST program (35). Accession web site:
http://www.ncbc.nlm.nih.gov/BLAST.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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Isolation of differences
Representative RAP-PCR fingerprints from the control and
hormone-treated kidneys were prepared at two cDNA concentrations and
run side by side on a polyacrylamide gel and compared for differences
(Fig. 1B
). Only those bands that were consistently differential between
DHT- and sham-treated mice at both RT concentrations were cut from the
sequencing gels, reamplified, and used as probes in filters containing
3 µg PolyA+ RNA from kidneys of sham- and DHT-treated
female mice. Approximately, 60% of the selected bands proved to be
differential after Northern blot analysis, when normalized with the
GAPDH internal control gene.
Since each PCR product might contain more than one gene and because, in
some instances, more than one transcript was found on Northern blots,
bands were cloned, single colonies were selected, and individual clones
were assayed again, in similar filters, by Northern blot analysis.
Using this technique, up- and down-regulated products were found, as
shown for clones 1–1, 2–1, and 3–1, respectively (Fig. 1C). Sequence
analysis and comparison against GenBank and dbEST databases revealed
that clones 1–1, 2–1, and 3–1 correspond to the interleukin-6 signal
transducer (IL-6ST), kidney androgen-regulated protein (KAP) and
testosterone 16--hydroxylase (16- OH) genes, respectively (Table 1).
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Two successive rounds of subtraction and amplification using
hybridization tester-driver ratios of 1:100 and 1:800 generated a
second difference product (DP2) consisting of bands ranking from
820–270 bp in size (Fig 2, A and B).
These bands were excised from the gel, subcloned in the
BamHI site of the pBluescript II SK+ vector, and
sequenced for further identification. A third difference product (DP3)
was generated but did not identify any additional products. Eight of
nine differential products from DP2 were cloned, and single colonies
were selected, sequenced, and compared against GenBank and dbEST
databases using the BLAST program.
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, clones 2–1 and 8–1 were both part of the SA gene
and 5–1 and 6–1 were derived from the cytochrome CYP4B1 (CYP4B1)
gene, indicating that different clones from different bands can contain
contiguous DpnII fragments of the same gene. Clone 7–1 was
identified as the organic anion transporter (OATP), clone 9–1 as an
endogenous murine leukemia virus (MuLV), and clone 4–1 lacked
similarity to any database sequence. The sequence was sent to
theGenBank database and has been named MJAM. No obvious open reading
frame was found in this sequence, and the six possible reading frames
did not show any homology with known proteins. It is therefore possible
that this fragment is derived from a noncoding portion of the gene and
that other regions of the same gene may be contained in the databases.
The remaining clone 3–1 was histone H10 and was found not
to represent a genuine difference between the populations. It should be
noted that a single band might contain more than one clone and that
additional products may still be identified from this experiment.
Expression levels of the androgen-induced KAP gene in mouse
kidney are very high, and its cDNA contains four DpnII
sites. Since no clones were identified as KAP, we performed Southern
hybridization analysis of difference products DP1 and DP2 with a
radiolabeled KAP cDNA probe. KAP specifically hybridized to a band of
420 bp in DP2. This indicates that PCR amplification has probably
favored the KAP amplicon found in this particular band and that the
basal levels of expression of this gene are sufficient to compete out
most of the DpnII fragments (Fig. 2C).
We next performed Northern blot analysis to confirm that the
cDNARDA difference products truly represented the expression levels
seen in vivo. We found that transcripts recognized by clones
2–1, 5–1, 7–1, and 9–1 (SA, CYP4B1, OATP, and endogenous murine
leukemia virus, respectively) are strongly induced by androgens, since
no mRNA expression is detected in kidneys of sham-treated females, at
the exposure times studied. Clone 4–1 (MJAM) detects two coordinately
expressed androgen-inducible products that are also expressed under
basal conditions (Fig. 3).
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). The same filters were then used to
analyze the expression of target genes, and the results clearly
demonstrate flutamide sensitivity of all products, showing that all are
truly and coordinately regulated by androgens (Fig. 4B).
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). This
establishes that these genes are androgen-regulated at physiological
doses.
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); CYP4B1 is expressed in
kidney and lung; the 16-OH and OATP are expressed in kidney and
liver; and MJAM and IL-6ST are widely distributed. Interestingly, the
kidney expression of the SA and OATP genes is androgen-dependent, since
only trace amounts of their mRNAs are detectable in kidneys of
sham-treated female mice; a basal expression inducible by androgens is
also observed for the OATP gene in liver. The CYP4B1 gene shows a
nonandrogen basal expression that is inducible by androgens in kidney
and lung, although induction in kidney is more prominent. The IL-6ST
gene, which is expressed in every tissue tested, appears not to be
regulated by androgens in tissues such as liver, brain, and cerebellum;
is repressed by androgens in spleen and heart; and is androgen-induced
in kidney and lung. A very interesting finding is the fact that only in
kidney and under the exclusive presence of androgens, two different
mRNA species appear for the IL-6ST gene, in addition to the 7- and
10-kb mRNAs that are present, at different ratios, in every tissue
tested. The unknown gene identified in this study, MJAM, is also
inducible by androgens in kidney and lung. Finally, while expression of
the 16-OH gene is repressed by androgens in kidney, it appears to be
up-regulated in liver. All hybridization signals have been normalized
with the signal obtained for the housekeeping internal GAPDH control
gene.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For several years, our laboratory has been involved in the study of the regulation of the KAP gene, and a cell-specific multihormonal regulation of its expression has been reported (22, 37). Thyroid hormone controls KAP mRNA levels in the epithelial cells of proximal tubules, specifically in the pars recta or S3 segment (23), while androgens are responsible for expression in the pars convoluta or segments S1 and S2 of the same tubules (16). From these studies, we have also learned that the KAP androgen-dependent cortical expression depends on the presence of thyroid hormone (24) and that estrogens further induce its expression in the S3 cells (22).
Identification of putative common regulatory elements in the promoters of androgen-regulated genes has been troublesome. Androgenic inducibility of the KAP gene is very different from that exhibited by other classic androgenic markers of mouse kidney, and both kinetics of induction and patterns of expression vary with strain and tissue specificity. Consequently, in the absence of an appropriate androgen-responsive cell culture system, the elements responsible for the generation of an androgen-regulated phenotype in mouse kidney have been very difficult to describe. For this reason, we have undertaken a project aimed at defining multiple new markers of androgen action in mice of the same strain, exposed to identical induction conditions. In this way, we hope to be able to compare regulatory elements and pinpoint common features.
We have identified several genes as being androgen-sensitive in the
mouse kidney. SA and OATP are the mouse counterparts of the human and
rat SA genes and the rat OATP gene, respectively. The genes coding for
CYP4B1, MuLV, 130-kDa subunit of the IL-6ST, and 16--OH correspond
to genes previously identified in the mouse. Our demonstration of
androgen induction of the OATP gene in mouse kidney tallies with the
recent report of its regulation by testosterone in rat kidney (38).
Analysis of tissue distribution and androgenic control of the genes
found has allowed us to classify them as kidney-specific (SA and KAP),
highly restricted (OATP, CYP4B1, and 16-OH), or widely expressed
(IL-6ST and MJAM). Promoter analysis of these kidney-specific genes
might allow further identification of enhancer sequences responsible
for tissue specificity, which would prove useful in transgenic
experiments.
Although SA and KAP genes share kidney specificity, they differ in
their regulation. While SA is practically not expressed in the absence
of androgens, KAP exhibits an important androgen-independent basal
expression that increases or diminishes in the presence or absence of
androgens, respectively. IL-6ST and CYP4B1 are widely expressed, but
their androgen regulation appears to be restricted to the kidney. The
fact that the MJAM is also regulated by androgens in lung, as are OATP
and 16-OH genes in liver, suggests that these tissues might share
common elements needed for androgenic control of expression. In
instances where an androgen-independent basal expression exists, it
will be necessary to define wether such expression is constitutive or,
as for the KAP gene, other hormones are involved in their
regulation.
The mechanisms by which androgens modulate the transcript levels of these genes is the subject of continuing research in our laboratory. Since members of the steroid/thyroid receptor superfamily can transactivate and also stabilize previously synthesized mRNAs, we are currently attempting to determine which of these genes are under androgen transcriptional control by performing run-on nuclear assays. We are also investigating whether androgen regulation of these genes is blocked by inhibitors of protein synthesis, as well as characterizing putative consensus sequences in their promoters. In this way, we hope to delineate the extent to which these genes are under direct androgen transcriptional control.
The physiological significance of androgen-inducible gene expression in the kidney is largely unknown since most of the target genes identified so far correspond to housekeeping genes and genes whose protein products have not been entirely characterized. We believe that at least three of the genes identified in this study, SA, CYP4B1, and IL6ST, may prove to be interesting from the pathophysiological perspective. The SA gene is a major component of an important system regulating blood pressure (39). Our finding that it is under very strong androgen control might be very important for understanding the hormonal control of certain forms of hypertension in which a sexually dimorphic pattern of blood pressure has been observed (40). We are currently trying to correlate levels of blood pressure, presence of androgens, and expression of the SA gene in kidneys of normal and hypertensive rats and mice.
The finding that expression of the CYP4B1 gene is induced by androgens in kidney is particularly interesting since Imakoa et al. (41) have reported that CYP4B1 plays a major role in the mutagenic activation of the potent procarcinogen, 3-methoxy-4-aminoazobenzene (41). Metabolism of this and others substrates, such as 2-aminofluoreno and 2-aminoanthracene, may affect the homeostasis of the kidney and its susceptibility to disease. Lung carcinomas exhibit higher levels of CYP4B1 mRNA than normal lung tissues (42), and we find provocative the possible association of the androgenic up-regulation of a member of the cytochrome P450 enzyme family in kidney with the well documented higher incidence of renal cell carcinomas in man than in woman. Interestingly, the great majority of these tumors develop from epithelial cells of proximal convoluted tubules, which are, in turn, the cellular targets for androgen action.
The IL-6ST gp130, although initially described as the IL-6 signal transducer, is the signal transducer protein for receptors recognizing IL-11, leukemia inhibitory factor, ciliary neurotrophic factor, oncostatin M, and the recently described cardiotrophin-1 (43). In relation to its tissue distribution, murine gp130 is ubiquitously expressed, and Saito et al. (44) have reported the existence of two species of mRNA (7 and 10 kb) with different ratios in each tissue examined. Our work shows the appearance of two new gp130 transcripts, exclusively in kidney and only under the presence of androgens. Although the physiological significance of our findings remains to be elucidated, it is interesting to determine whether these two new forms of gp130 also appear in androgen-exposed human kidneys and whether putative new forms of gp130 might modify the biological effects exerted by interleukin-6, which has been reported to be produced by some renal cell carcinomas and to be responsible for several paraneoplastic syndromes in the carcinoma (45).
In summary, the complementary use of two PCR-based methods for the identification of differential gene expression (cDNARDA and RAP-PCR) has proved to be successful in the identification of androgen-regulated genes in mouse kidney. Our work has provided new models for the study of androgen action in kidney at the molecular and pathophysiological levels.
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Acknowledgments |
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Footnotes |
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2 M. Jesús Meliá is a predoctoral recipient fellow (FPI)
from the Ministerio de Educación y Ciencia.
Received August 11, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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