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Baker Medical Research Institute (M.J.F., K.M., J.W.F., T.J.C.), Melbourne 8008, Australia; and Department of Medicine, University of California (A.B., T.M.P., D.P.), San Francisco, California 94143
Address all correspondence and requests for reprints to: Dr. David Pearce, Department of Medicine, Box 0532, 513 Parnassus Avenue, University of California, San Francisco, California 94143. E-mail: pearced{at}medicine.ucsf.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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Several aldosterone-responsive genes have been reported: for example,
the 
1- and ß1-subunits
of Na+/K+-adenosine
triphosphatase (9); the epithelial sodium channel (ENaC)
subunits , ß, and 
, which are responsive to aldosterone in rat
kidney (10) but differentially induced in distal colon
(11); and a factor dubbed channel-inducing factor, which
is aldosterone induced in colon but not in kidney (12).
There is, however, considerable evidence that most, if not all, of
these represent secondary rather than direct genomic effects of
aldosterone. Importantly, whether they are primary or secondary
response genes, they are induced relatively slowly, over hours to days,
whereas changes in Na+ transport begin in less
than 1 h. On the other hand, it has recently been reported that
aldosterone rapidly and directly induces transcription of the serum and
glucocorticoid induced kinase (SGK) gene, and that the encoded protein
SGK may play a central role in mediating early aldosterone effects by
stimulating ENaC-mediated sodium transport (13, 14).
Dexamethasone rapidly induces SGK in the collecting duct (A6) cell
line, as does aldosterone in the rat kidney collecting duct
(13), in cultured rabbit cortical collecting duct cells
(14), and in distal colon (15). In all of
experimental situations, however, the conditions were nonphysiological
due to the use of cultured cell systems, high hormone concentrations,
and/or synthetic glucocorticoid agonists such as dexamethasone.
Furthermore, although parameters in cultured cells that reflect
epithelial Na+ transport were measured, no
correlation with the physiologically relevant changes in urinary
Na+ and K+ in
vivo has been shown.
Hence, although these initial studies suggested that SGK is an aldosterone-induced mediator of epithelial Na+ transport in the kidney, they are primarily premised on in vitro studies and supraphysiological doses of aldosterone. The present studies were therefore designed to examine the SGK response to aldosterone in a more physiological context, to determine whether the time course and sensitivity of the SGK response are consistent with those of an essential regulator of ENaC activity. To this end we administered physiological doses of aldosterone to rats in vivo, formally eliminating the possibility of GR activation by the concurrent administration of the GR antagonist RU486 and measured SGK induction against urinary electrolyte responses.
Time-course and dose-response studies were performed in this model system, and SGK messenger RNA (mRNA) levels were determined in colon, kidney, and heart by Northern blot analysis. SGK protein levels in distal colon were estimated by Western blot analysis. In addition, kidneys from these time-course and dose-response studies were subjected to in situ hybridization analysis to establish more precisely the characteristics of the SGK response to aldosterone at the cellular level.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Kagawa bioassay
Male Sprague Dawley rats (100–120 g) were used. On the day of
experiment the bladder of each rat (n = 5–8/group) was emptied at
60 min by gentle suprapubic pressure and a whiff of ether, the urine
was discarded, and 3 ml 0.9% saline/100 g BW were injected ip. At time
zero the bladder was again emptied, and the urine generated was taken
as the pretreatment sample for determination of
Na+ and K+.
In Exp 1 at time zero six groups (n = 5–8/group) of rats were injected sc with 10 µg RU 486 plus 0, 0.1, 0.3, 1.0, 3.0, or 10 µg aldosterone/100 g BW. Urine from time zero until 60 min postinjection was discarded, and at that time animals were given a second ip injection of 0.9% NaCl solution (3 ml/100 g BW). The final urine collection for all animals was taken at 120 min, for determination of Na+ and K+ by flame photometry (IL943, Allied Instrumentation Laboratories, Milan, Italy).
In Exp 2, one group of rats (n = 5) was injected sc with 10 µg RU486 at time zero and five groups (n = 5–8/group) with 10 µg RU486 and 1 µg aldosterone/100 g BW. A second ip injection of 3 ml 0.9% saline/100 g BW was given 30 min before the final urine collection, which was at 30, 60, 90, 120, or 180 min postaldosterone; the final urine collection for the RU486 alone group was taken 30 min postinjection.
In Exp 3, rats were adx or sham operated. Adx rats were given saline, and all groups had ad libitum access to rat chow. Five days after adx, rats were anesthetized and implanted sc with mini osmotic pumps (Alzet model 2001, Alza Corp., Palo Alto, CA) to deliver either propylene glycol (sham operated and adx + vehicle control groups, four rats per group) or 10 µg/day aldosterone. In addition to the pumps, subgroups of rats (n = 4/group) also received a single sc injection of aldosterone (1 µg/100 g BW) or saline (controls). The miniosmotic pumps were presoaked in saline for 24 h and delivered either vehicle or aldosterone. Rats were killed 2 or 4 h after treatment; tissues were removed and processed appropriately for Western blot analysis.
Isolation of RNA and Northern blot analysis
Total RNA was extracted from kidney, colon, and heart tissue of
adult rats by homogenization in TRIzol reagent (Life Technologies, Inc., Grand Island, NY). Homogenates were
extracted with chloroform, and RNA was precipitated from the aqueous
phase with isopropanol. RNA pellets were washed in 70% ethanol, dried,
and finally redissolved in sterile water. For Northern blot analysis,
total RNA (15 µg) was separated in formaldehyde containing 1.2%
agarose gel and transferred to GeneScreen Plus (NEN Life Science Products) by capillary Southern blotting (17).
Filters were hybridized in 0.5 M
Na2PO4 (pH 7.2), 7% SDS,
and 2 mM EDTA at 68 C overnight with an antisense
32P-labeled rat SGK riboprobe and washed as
previously described (18). All filters were rehybridized
with a riboprobe to a complementary DNA for mouse
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to control for RNA
loading. All washed filters were exposed for 1–3 days, and levels of
SGK mRNA were analyzed on a phosphorimager (Fuji Photo Film Co., Ltd., Tokyo, Japan).
In situ hybridization
Frozen tissue sections (8 µm) were cut on a cryostat,
thaw-mounted on SuperFrost slides, fixed, acetylated, and hybridized as
previously described (13). A 671-bp fragment (nucleotides
314–985) of rat SGK was used as a probe. This probe does not
cross-hybridize to the other SGK isoforms (2, 3) as determined by
Blast search, and no other isoforms were detected on Northern blots.
Briefly, [33P]UPT-labeled antisense riboprobe
was synthesized with T3 polymerase from 1 µg plasmid linearized with
BamHI. Hybridization was performed in a hybridization
solution containing 50% formamide at 55 C for 16–18 h. Coverslips
were removed in 2 x SSC (standard saline citrate); sections were
treated with ribonuclease A for 30 min, washed in 1 x SSC and
finally washed in 0.1 x SSC at 65 C. They were then passed
through alcohol series, air-dried, and exposed to Hyperfilm. Slides
were dipped in Kodak emulsion (Eastman Kodak Co., Rochester, NY), exposed in the dark at 4 C for 10 days,
developed, and counterstained with hematoxylin and eosin.
Western blot analysis
Distal colon was homogenized in a Polytron (Brinkmann Instruments, Inc., Westbury, NY) for 15 sec in PBS supplemented
with 1 mM phenylmethylsulfonylfluoride, 0.5 mM
dithiothreitol, and 1 x protease inhibitors (Roche Molecular Biochemicals, Indianapolis, IN). The homogenate was
spun at 14,000 rpm for 30 min at 4 C, and the supernatant was collected
and stored in aliquots at -80 C until use. Protein concentrations were
estimated on each lysate with Bradford’s reagent (Bio-Rad Laboratories, Inc., Richmond, CA). Samples were separated on a
8% polyacrylamide gel and transferred electrophoretically to
nitrocellulose membranes (Micron Separations, Westboro, MA). Membranes
were immunoprobed with SGK antibody as previously described
(13). Subsequently, the membranes were stripped in
solution containing 62.5 mM Tris-Cl (pH 7.6), 2% SDS, and
100 mM ß-mercaptoethanol at 50 C for 30 min, blocked with
5% milk powder, and immunoprobed with actin antibody as described.
Statistical analysis
SGK/GAPDH mRNA levels and
Na+/K+ levels from Kagawa
bioassays were analyzed by one-way ANOVA and Tukey’s
post-hoc test, with statistical significance set at
P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), with levels doubling at doses of 3
and 10 µg aldosterone. In colon there was a trend toward increased
SGK/GAPDH ratios with progressive increase in the dose of aldosterone
used, although no dose of aldosterone showed a statistically
significant increase at 2 h; at the 10 µg dose of aldosterone,
mean values for SGK mRNA/GAPDH mRNA were double the control value (Fig. 1B).
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). In the cortex, hybridization
was significantly enhanced at all doses of aldosterone used, with
higher levels of hybridization over distal tubular areas of the cortex
detected at 0.1 µg aldosterone (Fig. 2B). Hybridization in the outer
medulla appeared to respond slightly to the lowest dose of aldosterone,
with uniformly scattered hybridization only slightly more intense at
this dose, although levels were considerably higher with 0.3 and 1 µg
aldosterone (data not shown). Whereas marked hybridization was seen in
the cortex at 0.1–0.3 µg aldosterone, medullary staining did not
appear maximal until a dose of 1 µg aldosterone was used. At higher
doses of aldosterone (3 and 10 µg), the hybridization pattern did not
differ significantly from that observed at 1 µg (data not shown),
although the clustering of SGK signal in both cortex (over distal
tubules) and outer medulla was more marked at the two higher doses of
aldosterone. Papillary hybridization in control sections (Fig. 2D)
appeared significantly more intense than in other areas of control
kidneys, and papillary signal intensity remained unchanged over the
range of doses of aldosterone tested. Taken together these results
indicate that even at low doses of aldosterone (0.1 µg) there is
significant induction of SGK mRNA in outer medulla and cortical
collecting duct, with papillary expression of SGK constitutively higher
but unresponsive to aldosterone.
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). No change in urinary sodium
concentrations (Na2/Na1; Fig. 3B) was seen until a dose of 0.3 µg
aldosterone was injected, which produced a halving of sodium levels; at
higher aldosterone doses urinary sodium concentrations fell to one
quarter of the control value. In contrast, urinary potassium
concentrations, as determined by the ratio K2/K1, rose to approximately
double the control level from the lowest dose (0.1 µg), reaching a
maximum level 4-fold the control value at 10 µg (Fig. 3C). The plot
of Na2/K2 was notable for the clear efficacy of 0.1 µg aldosterone on
this value (Fig. 3D), an effect that increased with increasing doses of
aldosterone.
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) and whole colon (Fig. 4B) within 60
min of injection, with levels approximately double those in control
rats killed at time zero. SGK levels in heart were 10 times lower than
those in kidney and did not change at the time points examined (data
not shown). The extent of induction of SGK mRNA by aldosterone appeared
similar in kidney and whole colon, with the maximum in kidney double
the control value (17 ± 3 at 90 min vs. 8 ± 1 at
time zero; P < 0.05) and that in colon almost double
(2.3 ± 0.3 at 60 min vs. 1.2 ± 0.2;
P < 0.05). At other time points examined, there was a
trend toward an increase in SGK mRNA over the control value,
but the levels did not attain statistical significance (Fig. 4, A and B).
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).
Hybridization to SGK mRNA is shown in both light- and darkfield at 0
and 60 min after injection of aldosterone in both cortex and medulla
(Fig. 5B, A–D). In the cortex hybridization was seen in both the
glomerulus and distal nephron, but was aldosterone responsive only in
the distal nephron (Fig. 5B, B and C). Administration of aldosterone
did not change hybridization to glomeruli at 30 min or any other time
point examined. Although SGK mRNA began to appear over few distal
tubules in the cortex by 30 min, no significant increase in
hybridization to SGK mRNA was seen at this time point in the outer
medullary collecting ducts or the inner medullary area. By 60 min,
however, substantial levels of hybridization to SGK mRNA were clearly
seen over many collecting tubules in both cortex and outer medulla
(Fig. 5B, B and C). At 90 and 120 min, SGK hybridization patterns did
not differ significantly from those at 60 min, although clustering of
signal in outer medulla increased at 90 and 120 min (data not shown).
High levels of SGK expression were observed in inner medulla/papilla,
with levels of expression remaining constant despite aldosterone
treatment, consistent with a recent report that SGK mRNA remains
unchanged in papilla but is responsive to aldosterone treatment in
cortex and outer medulla, as determined by Northern blot analysis
(19).
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). Changes in the urinary sodium ratio
Na2/Na1, taken pre- and postaldosterone treatment (Fig. 6B), did not
appear until the 90 min point, when a halving of sodium excretion was
seen. This decrease was sustained for each of the collection periods up
to 180 min. In contrast, potassium excretion, as determined by the
K2/K1 ratio, rose progressively from the second collection period
(30–60 min) postaldosterone treatment, reaching maximum levels at 120
min.
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ENaC expression, whereas
expression of these subunits remained unresponsive in more proximal
descending colon (11). In addition, SGK message was
induced in distal descending colon 2 h after aldosterone
administration. The modest effect of aldosterone on SGK induction in
whole colon described above probably reflects this graduation in
response to aldosterone throughout the colon. We therefore examined the
status of SGK protein in distal descending colon (Exp 3) in adx,
sham-operated, and adx plus aldosterone-treated rats. Aldosterone
treatment resulted in a significant increase in immunoreactive SGK
protein 2 and 4 h after hormone treatment (Fig. 7), consistent with the induction of SGK
protein seen 2 h after dexamethasone treatment in A6 cells
(13).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In previous studies of adrenalectomized rats (13) a high dose (50 µg/100 g BW) of aldosterone was used for in situ hybridization studies. At this dose, the effect of aldosterone could possibly be mediated via GR, for which aldosterone has low, but significant, affinity. Actions on urinary sodium and potassium excretion via GR are not merely a formal possibility; in both cultured cortical collecting tubule preparations (3) and adx rats (4) highly selective glucocorticoids have been shown to be equipotent to aldosterone when their metabolism by 11ßHSD2 is blocked. In addition, the original cloning of Xenopus SGK from A6 cells exploited this nonselectivity, with dexamethasone used as a ligand to induce SGK expression via GR. Very recently, Brennan and Fuller have shown dexamethasone to have effects on SGK mRNA induction in rat kidney and colon at least equal to those of aldosterone (15). For this reason we included RU486 with aldosterone in all studies to minimize the possibility of substantial GR occupancy (22, 23) and activation by aldosterone, however unlikely that might be at the doses used and given its relatively low affinity for GR. Further evidence for aldosterone acting via MR comes from studies in which administration of RU26752, an MR antagonist, prevented aldosterone-mediated induction of SGK (19).
In terms of both mRNA levels and urinary electrolytes, the ED50 for aldosterone appears to be about 0.3 µg/100 g BW, with the bioassay in this instance proving a more precise measurement system. This reflects in large part the fact that relatively high levels of SGK are expressed in renal glomeruli, which do not respond to adrenalectomy or aldosterone administration; there is, therefore, a high background level of SGK expression in the kidney, against which probably substantial increases in a relative minority of cells must be set. This is very clearly shown by the results of the in situ studies at the lower end of the dose range used, at shorter time points. Although such data are semiquantitative at best and not easily subjected to statistical analysis, they provide graphic evidence for a clear induction of SGK in cortical collecting duct and papilla at the lowest dose of aldosterone used (0.1 µg/100 g BW) and in all tissues at 0.3 µg/100 g BW.
The time-course studies described in this paper confirm, both in situ and by Northern blot assay, that SGK is rapidly induced, and that over the 3-h period of study chosen, SGK mRNA levels in kidney are returning to baseline at a time when the effect on urinary electrolytes (presumably via ENaC activated by the induced SGK) remains high. Again, the in situ time-course studies show clear effects in a range of renal target tissues at 30 min, before any effects on urinary Na+ or K+ can be seen, as expected. The effects of aldosterone on urinary K+ in this study appear to precede those on Na+. This may reflect an effect of aldosterone that is independent of SGK, given the clear demonstration of the inactivity of SGK in terms of ROMK2 activation (13), although further examination of electrolyte excretion (for example, urinary Na excretion volume or urinary Na under conditions of collecting duct impermeability to water) will be required to explore the mechanisms underlying this difference. A similar disjunction in the time course of mineralocorticoid effects on urinary Na+ and K+ excretion has previously been described by Morris et al. (24).
In the whole colon, the changes paralleled those in the kidney, consistent with the recent report that SGK mRNA is induced by aldosterone in distal colon (15, 19). It has also been shown that the distal descending colon is sensitive to nanomolar levels of aldosterone, and that expression of other aldosteron- responsive genes (ENaCs) is differentially regulated over the course of the distal colon (11). Our studies used whole colon, which may thus have contributed to the relatively modest response observed. However, when late distal colon was examined, we observed a robust induction in SGK protein after aldosterone treatment. Recently, SGK protein has been shown to be induced in the distal nephron by aldosterone (25) in mouse kidney. It is thus clear that the epithelial response of SGK in vivo to aldosterone can be extended to the colon as an additional epithelial tissue, suggesting that SGK may be an essential mediator of aldosterone-stimulated ion transport in all classical mineralocorticoid target tissues.
Although MR have been described in a variety of other tissues (26), as has SGK (27), it is possible that SGK induction may be a uniquely epithelial response to increased aldosterone; one fragment of evidence in support of this are the unchanged cardiac levels of SGK in the present studies over the fairly substantial (0.1–10 µg/100 g BW) range of aldosterone doses used. It is also possible that other isoforms of SGK (28) are present in the heart, which may be responsive to aldosterone treatment, but that their mRNAs are undetectable with the probe used in this study. Finally, it is clear that these studies on MR-mediated effects of aldosterone on SGK do not exclude the possibility of additional modulators of enzyme activity in the kidney and colon.
Other agents are known to induce SGK expression. Whereas SGK was initially identified as a SGK from a rat mammary tumor cell line (27), in the brain, SGK is not responsive to glucocorticoid treatment, but is induced after central nervous system injury (29). Whereas in liver cells SGK is responsive to hyperosmotic shock (21), in A6 cells SGK is responsive to osmotic shock (Rozansky, D. J., and D. Pearce, unpublished results) as well as to glucocorticoids (13). SGK when coexpressed with ENaC subunits in Xenopus oocytes results in a marked increase in the amiloride-sensitive sodium current (13), and similar observations have been made by others (14, 19). SGK is phosphorylated at specific threonine residues (30), and this is mediated via the action of the phosphatidylinositol 3-kinase signaling pathway (31, 32). Although prevention of phosphorylation of SGK by inhibitors of phosphatidylinositol 3-kinase results in inhibition of hormone-induced activation of the sodium current (31, 32), the substrate(s) phosphorylated by SGK remains unidentified, and the exact mechanism by which SGK augments ENaC-mediated increases in sodium transport remains to be determined.
In summary, the present studies confirm that SGK is an immediate early gene regulated by aldosterone via MR, with responses to aldosterone at low (0.1 µg/100 g BW) doses and within 30 min of administration. In terms of both mRNA levels and the urinary electrolyte response, the ED50 for aldosterone is on the order of 0.3 µg/100 g BW, as a single sc dose. Kagawa bioassay changes, in terms of urinary electrolyte ratios, follow SGK mRNA profiles in a temporal sense, with some evidence for a slightly earlier effect on urinary K+ than Na+; colonic levels of SGK mRNA appear lower than those in the kidney, and both mRNA and protein levels change in parallel in response to aldosterone, in contrast with those in the heart. Additional studies of SGK activation and other aldosterone-regulated genes and their products, are required for a more comprehensive understanding of aldosterone action in epithelial and nonepithelial target tissues.
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Acknowledgments |
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Footnotes |
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Received August 4, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ß, and subunit
proteins in rat kidney. J Clin Invest 104:R19–R23
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