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From the * Departments of Biochemistry and
Urology, Yamagata University School of
Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan; and
Department of Biochemistry, Osaka University
Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| Correspondence to: Junichi Fujii, Department of Biochemistry, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata 990-9585, Japan (e-mail: jfujii{at}med.id.yamagata-u.ac.jp). |
| Received for publication December 18, 2001; accepted for publication April 12, 2002. |
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Abstract |
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Key words: Epididymis, prostate, seminal vesicle, vas deferens, Sertoli cells
Because sorbitol diffuses much more slowly than glucose and fructose, it tends to accumulate in cells and to increase the osmotic pressure. One of the physiological roles of AR in some cells appears to be the production of sorbitol and the protection of cells from high osmotic pressure under hyperosmotic conditions (Burg, 1995). However, abnormally high concentrations of sorbitol produced by enhanced AR activity under hyperglycemic conditions are believed to lead to diabetic complications in some tissues such as peripheral neurons, kidney, and eye (Kinoshita and Nishimura, 1988). Enhanced AR activity also causes a reduction-oxidation (redox) imbalance by altering the NADPH:NADP+ ratio (Bravi et al, 1997) and triggers damage to cells with a low redox capacity, such as pancreatic ß-cells (Hamaoka et al, 1999). Hence, the properties of AR and its gene expression in diabetes have been extensively investigated from the pharmacological point of view (Tomlinson et al, 1994; Yabe-Nishimura, 1998). In addition, some other functions, including detoxification of cytotoxic carbonyl compounds, have been established for some members of the aldo-keto reductase family, to which AR belongs (Flynn, 1982; Jez et al, 1997; Fujii et al, 1999).
Because the enzymes in this superfamily have homologous amino acid sequences (Bohren et al, 1989) and recognize similar chemical structures of substrates, it is not possible to specify its gene products by measuring its activity alone. Thus, a reliable probe, a complementary DNA (cDNA) or a specific antibody, must be applied in order to evaluate the contribution of AR to certain physiological functions. Although the existence of this pathway in the accessory glands has been known for long time, within the male reproductive system, immunohistochemical localization of AR has been carried out only in testis (Ludvigson and Sorenson, 1980; Ludvigson et al, 1982).
SDH, on the other hand, belongs to a medium-chain dehydrogenase/reductase family, and its enzymatic activity can be distinguished from other members of the family using sorbitol as the substrate. Whereas histochemical studies have been reported for SDH in some tissues (Riva and Usai, 1970; Micucci et al, 1971), no immunohistochemical study has been carried out to specify cells that express SDH in the male reproductive system and accessory glands.
In previous studies we reported the establishment of an anti-rat AR antibody, which was used to detect expression of the protein in rat hepatoma tissues and cell lines (Takahashi et al, 1995; 1996), and an anti-rat SDH antibody (Hoshi et al, 1996). In this study, we report the use of these antibodies to identify cells that express these enzymes in the male reproductive tract (ie, testis, epididymis, vas deferens, prostate, and spermatozoa) in rats.
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Materials and Methods |
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Testicular Cell Culture and Protein Extraction
A male Wister rat (40 days) was killed by diethyl ether anesthesia, and
testicular cells were isolated as reported by Kaneko et al
(2002). After decapsulation of
the testes, seminiferous tubules were minced using scissors, and incubated in
phosphate-buffered saline (PBS; 8 mM sodium phosphate buffer, pH 7.4
containing 137 mM NaCl and 2.7 mM KCl) containing 0.25% Type I collagenase
(Wako, Osaka, Japan) at 32.5°C for 15 minutes. Seminiferous tubules were
washed with PBS once and then incubated in PBS containing 0.25% trypsin
(Difco, Detroit, Mich) at 32.5°C for 15 minutes. After adding fetal bovine
serum (FBS) to a concentration of 10%, the cell suspension was filtered
through stainless mesh (Nonaka Rikaki, Tokyo, Japan) to remove aggregates and
tissue debris. The cells were cultured in an equal mixture of Ham F12 (ICN
Biomedicals, Aurora, Ohio) and Lebovitz L15 medium (Dainippon Pharmaceutical,
Osaka, Japan) supplemented with 100 U/mL penicillin G, 100 µg/mL
streptomycin, 15 mM Hepes (pH 7.3), and 10% (vol/vol) FBS for 4 days at
32.5°C with 5% CO2 in humidified conditions. After harvesting
the cells with a silicon scraper, they were washed with PBS twice and
sonicated in an extraction buffer (25 mM Tris-HCl pH 7.4, 50 mM NaCl, 10
µg/mL aprotinin [Wako, Osaka, Japan], 10 µg/mL leupeptin [Wako], and
0.57 mM phenylmethanesulfonyl fluoride hydrochloride [Wako]). The soluble
fractions were subjected to protein analysis after centrifugation at 10 000
x g for 20 minutes at 4°C.
Preparation of Tissue Proteins
Testicular tissues in 1.5-mL tubes were homogenized in 4 volumes of the
above extraction buffer with a Micro Multi Mixer (Ieda Trading, Tokyo, Japan)
for 1 minute on ice. The supernatant was collected after centrifugation at 10
000 x g for 20 minutes. Spermatozoa were collected from the
epididymis of an 8-month-old adult rat. After washing twice with a large
excess of PBS, the spermatozoa were sonicated with a Microson Ultrasonic Cell
Disruptor (Misonix, Farmingdale, NY) 3 times for 20 seconds on ice in the
extraction buffer, and centrifuged. A bicinchoninic acid (BCA) kit (Pierce,
Rockford, Ill) was used to determine protein concentrations using bovine serum
albumin as the standard.
Enzyme Assays
Aldo-keto reductase activity was determined as described previously
(Takahashi et al, 1993). The
rate of decrease in the absorbance of NADPH at 340 nm was measured at room
temperature with methylglyoxal (MG), a common substrate for the aldo-keto
reductase family, as the substrate. The assay mixture contained 100 mM sodium
phosphate pH 7.0, 0.1 mM NADPH, and 10 mM MG. One unit of the activity was
defined as the amount of the enzyme that catalyzed the oxidation of 1 µmol
of NADPH per minute. SDH activity was determined as described previously
(Hoshi et al, 1996). The assay
mixture contained 100 mM glycine-KOH pH 9.0, 0.5 mM NAD+, and 100
mM sorbitol. The rate of increase in the absorbance of NADH at 340 nm was
measured spectrophotometrically at 22°C. One unit of SDH activity was
defined as the amount of enzyme that catalyzed the reduction of 1 µmol of
NAD+ per minute. The specific activity was expressed as units per
milligram of protein. Assays were performed on 3 independent samples, and
means plus standard deviations (SDs) are shown.
Sodium Dodecyl Sulfate—Polyacrylamide Gel Electrophoresis and
Western Blot Analysis
Protein samples were subjected to 10% or 12% sodium dodecyl
sulfate—polyacrylamide gel electrophoresis (SDS-PAGE) and then
transferred to Hybond-P (Amersham Pharmacia, Piscataway, NJ) under semidry
conditions by means of a Transfer-blot semidry transfer cell (Bio-Rad,
Hercules, Calif). After blocking by incubation with 5% skim milk in
Tris-buffered saline (TBS) containing 0.1% Tween-20 for 2 hours at room
temperature, the membranes were reacted for 12 hours at 4°C with a 1:10
000 dilution of the antibodies to AR
(Takahashi et al, 1995) and
SDH (Hoshi et al, 1996). After
washing with TBS containing 0.1% Tween-20, the membranes were incubated for 1
hour with a 1:2000 dilution of peroxidase-conjugated goat anti-rabbit
immunoglobulin G (IgG) (Santa Cruz Biotechnology, Santa Cruz, Calif). After
washing, the chemiluminescence method was employed to detect peroxidase
activity (ECL kit; Amersham Pharmacia). When the other antibody was applied to
the same membrane, it was stripped in 100 mM 2-mercaptoethanol, 2% SDS, and
62.5 mM Tris-HCl pH 6.8 at 60°C for 30 minutes, and washed twice with TBS
containing 0.1% Tween-20 at room temperature.
Preparation of Total RNA and Northern Blot Analysis
Total RNAs were prepared from various rat tissues as described previously
(Kanek et al, 2001), and 5 or 10 µg were electrophoresed on a 1% agarose
gel containing 2.2 M formaldehyde. The size-fractionated RNAs were transferred
onto a Hybond-N membrane (Amersham Pharmacia) by capillary action. After
hybridization with the 32P-labeled rat AR or SDH cDNA probes at
42°C in the presence of 50% formamide, the membranes were washed twice for
20 minutes at 55°C in 2x standard saline citrate (SSC; 1x SSC
= 150 mM NaCl and 15 mM sodium citrate pH 7.5) containing 0.1% SDS and then
twice in 0.2x SSC. Kodak XAR films (Kodak, Rochester, NY) were exposed
with an intensifying screen at -80°C.
Immunohistochemistry
Immunohistochemical analyses of the tissues were carried out essentially as
described previously (Kaneko et al,
2001). Paraffin sections (4 µm thickness) were deparaffinized
in xylene and hydrated in a series of graded ethanol solutions. After
hydration, endogenous peroxidase was inactivated in 0.3% hydrogen peroxide in
methanol. Prior to immunostaining, the nonspecific binding of the antibody was
blocked with 2% (vol/vol) swine serum (DAKO, Carpinteria, Calif) in PBS for 10
minutes. The sections on the slides were immersed in 50 mL of a solution
containing the antibody specific for 1:5000 diluted AR
(Takahashi et al, 1995) or
1:2000 diluted SDH (Hoshi et al,
1996), and then incubated at room temperature in a humid chamber
overnight. Following three consecutive washes in PBS for 5 minutes each, the
sections were incubated at room temperature for 30 minutes with horseradish
peroxidase-conjugated goat anti-rabbit IgG polymer (DAKO). To visualize the
signals, the reaction was completed by incubating the sections in
diamino-benzidine tetrahydrochloride reaction reagent (DAKO) for several
seconds. The resulting slides were then washed in water, dehydrated by them
passing through a series of graded ethanol solutions, and mounted. Photographs
were taken using a digital camera under light microscopy (Olympus BX50, Tokyo,
Japan).
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Results |
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Levels of AR and SDH Proteins and Messenger RNAs
To evaluate the levels of these enzymes in tissues and spermatozoa, we
carried out a Western blot analysis with the antibodies raised against rat AR
and SDH. The band with a relative molecular mass of 36 x
10-3, corresponding to the AR protein, was observed in all tissues
except for the prostate gland (Figure
2a). This can be explained by the presence of other aldo-keto
reductases, as discussed below. The band with relative molecular mass of 39
x 10-3, corresponding to SDH protein, was also observed in
all tissues except for the prostate gland, and their levels roughly matched
the SDH activity. Low levels of AR and SDH proteins were detected in the
prostate gland by a longer exposure. Although the content of AR protein was
detectable only by a longer exposure, a relatively high level of the SDH
protein was clearly present in spermatozoa. A Northern blot analysis, which
was carried out for total RNAs extracted from the same tissues, showed some
surprisingly inconsistent results between the proteins and mRNAs for AR and
SDH (Figure 2b).
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Immunohistochemical Distribution of AR and SDH in Adult Rats
We employed immunohistochemical analyses of AR and SDH in order to
determine their distribution in the male reproductive tract of adult rats
(Figures 3 and
4). Testis immunoreactivity to
the anti-AR antibody was strong in Sertoli cells, but weak in spermatogenic
cells, except for the nuclei of elongating spermatids and spermatozoa
(Figure 3a and c). However, by
an unknown reason, spermatozoa in epididymides were not reactive to the
anti-body (Figure 3e). The
anti-SDH antibody reacted with most spermatogenic cells, except the Sertoli
cells in seminiferous tubules (Figure 3b
and d). We examined the expression of SDH at 14 cycle stages of
seminiferous epithelium of the rat and correlated it to pachytene
spermatocytes and elongating spermatids. Stronger staining by the anti-SDH
antibody was observed after spermatids had elongated, and in residual bodies.
The specific stage at which AR and SDH mRNAs were present was examined by in
situ hybridization, and the findings showed that both mRNAs were present,
mainly in spermatocytes, and were barely detectable in spermatids (data not
shown). To determine the distribution of SDH in spermatozoa, we carried out
immunofluorescent staining of spermatozoa from the epididymis. Because entire
spermatozoa were stained evenly, there appeared to be no specific distribution
for SDH (data not shown). Thus, AR was present mainly in Sertoli cells in
testes and not in sperm, whereas SDH is present in most spermatogenic cells
and spermatozoa. The epithelia of the epididymides, vas deferens, seminal
vesicles, and prostate glands were strongly stained for the AR antibody
(Figure 3e;
Figure 4a, c, and e). Essentially the same tissues were also stained with the SDH antibody, as seen
in consecutive sections (Figure
3f; Figure 4b, d, and
f). Contrary to our findings in the testes, the two enzymes
constituting the polyol pathway were coordinately expressed in these tissues.
Positive signals to both antibodies were found mainly in the cytoplasm, except
for the epididymis epithelia, in which some nuclei were strongly stained.
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Confirmation of Cells Expressing AR and SDH in Primary Testicular
Culture
To identify cells that express AR and SDH more clearly, testicular cells
were separated under culture conditions. Because Sertoli cells attach and grow
on a conventional plastic plate, but spermatogenic cells do not, they could be
isolated by being plated on a dish, followed by separation of the culture
medium containing floating cells from the attached cells.
Figure 5a shows data on the
morphology of the cells thus separated. The floating cells with a round shape
corresponded to spermatogenic cells, whereas the attached and spread cells
with an amorphous shape were Sertoli cells. AR and SDH expression, as judged
by immunoblotting, confirmed that AR was expressed by both Sertoli cells and
spermatogenic cells, whereas SDH was highly expressed only by germ cells
(Figure 5b).
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Changes of AR and SDH Expression in Testes during Sexual
Maturation
To examine the relationship of the expression of AR and SDH with sexual
maturation, Western blot and Northern blot analyses as well as enzyme assays
were carried out for soluble proteins from 14-day, 21-day, 25-day, 30-day, and
13-week rat testes (Figure 6).
When the anti-AR antibody reacted to the blotted membrane, high levels of the
AR protein were found in all samples examined. The intensity of the bands
appeared to change only slightly during sexual maturation and corresponded to
the observed activity. After stripping the AR antibody from the membrane, the
antibody to SDH was applied. The intensities of these bands increased during
the sexual maturation of adult testis at the maximal level. When Northern blot
analyses were carried out using specific rat cDNAs for AR and SDH, essentially
the same tendency was observed for both mRNAs, except in 13-week testes. To
examine the types of cells that express AR and SDH during sexual maturation,
we also carried out immunohistochemical analyses of testes at the
corresponding stages (data not shown). In seminiferous tubules, Sertoli cells,
but not spermatogenic cells with large nuclei, were stained by the anti-AR
antibody at 2 weeks of age. During sexual maturation, spermatogenic cells
proliferated and the cells that stained strongly with the AR antibody were
relatively few in number. The anti-SDH antibody, on the contrary, reacted with
most types of spermatogenic cells in the seminiferous tubules at all
developmental stages examined.
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Discussion |
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Here we observed the codistribution of AR and SDH, which together are responsible for fructose production in the epithelial cells of epididymis, seminal vesicle, vas deferens, and prostate gland (Figure 3). Thus, all tissues in the male reproductive tract, except the testis, were found to have the ability to produce sorbitol and fructose. A physiological role of these enzymes in these tissues would be, at least in part, to produce sorbitol and fructose, and to release these products into the seminal plasma. The enzymatic activity of aldo-keto reductases and SDH were undetectable in the prostate gland (Figure 1), although both AR and SDH were clearly present by longer exposure of the Western blot. This may be in part due to the extraction efficiency of proteins from tissues. Because the prostate gland is soft tissue, most proteins could be extracted and the enzyme levels became relatively low. In addition, contents in the glands can be accumulated until they are released, whereas tubular fluids continue to change. Thus the specific activities of the enzymes do not always correlate with the levels of products in the fluids or secretions.
Although high levels of enzymatic activities were found in the testis (Figure 1), the distribution of these enzymes was quite different among the cell types. Whereas SDH was mainly expressed in spermatogenic cells, AR was present at high levels in Sertoli cells and in elongated spermatids, and other spermatogenic cells as well (Figure 3). AR is not expressed in some tissues, such as liver, and thus is not coordinated with SDH, which is present at high levels (Takahashi et al, 1995; Hoshi et al, 1996). Although a function of AR in conjunction with SDH is to produce fructose, it has other roles to play, such as to detoxify carbonyl compounds. substrates for the reducing activity of AR include active steroid hormones and their metabolites, such as progesterone and isocorticosteroids (Wermuth and Monder, 1983; Warren et al, 1993); carbonyl compounds caused by the glycation reaction, such as MG and 3-deoxyglucosone (Vander Jagt et al, 1992); and highly toxic compounds produced by lipid peroxidation, such as 4-hydroxynonenal and acrolein (Kolb et al, 1994; Vander Jagt et al, 1995). Male reproductive tracts are exposed to high concentrations of steroid hormones, oxidative stress caused by active metabolism, and the glycation reaction, as the result of high concentrations of reducing sugars. Thus, Sertoli cells, which are enriched in AR, as well as the epithelia, would also function to detoxify various carbonyl-containing metabolic products. Other aldo-keto reductases, in addition to AR, are also present in the reproductive tract (Lefrancois-Martinez et al, 1999; Nishi et al, 2000). Detoxification of the harmful carbonyl compounds by AR would also occur in these tissues.
Under hyperglycemic conditions, dysfunction occurs in the male reproductive tract, including testis (Sexton and Jarow, 1997), and abnormal sorbitol accumulation has been demonstrated in accessory glands (Paz et al, 1980). A stage-specific increase in apoptotic cell death of germ cells is observed in seminiferous tubules in animals with diabetes (Sainio-Pollanen et al, 1997). AR inhibitors are commonly used therapeutically to treat diabetic complications (Tomlinson et al, 1994). However, inhibition of AR and other aldo-keto reductases may also impair the function of male reproductive tissues by permitting toxic carbonyl compounds to accumulate.
Because SDH activity increases in parallel with the postnatal development of the testes, the SDH level has been used as an indicator of secondary maturation of sex organs (Mills and Means, 1972). An increase in SDH proteins around prepubertal and postpubertal testes was observed by Western blotting (Figure 6). Because the turnover rate of spermatogenic cells becomes enhanced after sexual maturation, the extremely high level of SDH mRNA would be due to the continuous proliferation of the spermatogenic cells. On the contrary, because AR was expressed both in Sertoli cells and spermatogenic cells, its level would be coincidentally maintained at a near constant level. In mature testis, the content of SDH increases during spermiogenesis and is maintained at high levels in spermatozoa and residual bodies (Figure 3). Although other genes that are translatable at the haploid stage show similar expression profiles, they are generally not expressed in other tissues or at the diploid stage of spermatogenic cells (Hecht, 1990). SDH appeared to remain in the residual body after completion of spermiogenesis, but large parts are also carried over to spermatozoa (Figures 1 and 3). Sorbitol is the major carbohydrate in uterine fluids of the bovine (Suga, 1975). A function of SDH retained in spermatozoa appears to convert sorbitol in seminal plasma and uterine fluid to fructose, which represents an energy source (King and Mann, 1959; Frenkel et al, 1975). There appear to be some conveniences for spermatozoa to utilize sorbitol or fructose. Because spermatozoa contain only a slight amount of cytosol, the glycolytic pathway would not be a major energy source. Fructose metabolism is known to be faster than that of glucose because it bypasses a rate-determining step composed of phosphofructokinase. In addition, resultant NADH as the byproduct of the SDH reaction can donate electrons to the electron transport system to synthesize adenosine triphosphate. Thus, from an energetic point of view, utilization of sorbitol or fructose is beneficial for spermatozoa.
In conclusion, sorbitol and fructose are produced in most male reproductive tracts via catalysis by AR and SDH. Distinct cellular distribution of these enzymes in testis would reflect their individual and beneficial functions. A function of AR in Sertoli cells would be to detoxify various carbonyl compounds that are cytotoxic. SDH, which is elevated in elongated spermatids and is carried over to spermatozoa, leads sorbitol to the glycolytic pathway via fructose.
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Acknowledgments |
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Footnotes |
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 M. D. Vibranovski, L. B. Koerich, and A. B. Carvalho Two New Y-Linked Genes in Drosophila melanogaster Genetics, August 1, 2008; 179(4): 2325 - 2327. [Abstract] [Full Text] [PDF]
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G. Frenette, M. Thabet, and R. Sullivan Polyol Pathway in Human Epididymis and Semen J Androl, March 1, 2006; 27(2): 233 - 239. [Abstract] [Full Text] [PDF]
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G. Frenette, C. Lessard, E. Madore, M. A. Fortier, and R. Sullivan Aldose Reductase and Macrophage Migration Inhibitory Factor Are Associated with Epididymosomes and Spermatozoa in the Bovine Epididymis Biol Reprod, November 1, 2003; 69(5): 1586 - 1592. [Abstract] [Full Text] [PDF]
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