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*
Department of Anatomy, Catholic University of Korea, Seoul,
Korea
Division of Nephrology, School of Medicine, The Johns Hopkins University,
Baltimore, Maryland.
Address correspondence to Dr. H. Moo Kwon, 963 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-614-0085; Fax: 410-614-5129; E-mail: mkwon{at}jhmi.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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The accumulation of compatible osmolytes is secondary to stimulation of transporters (4), the sodium/myo-inositol cotransporter (SMIT) and the sodium/chloride/betaine cotransporter (BGT1), and aldose reductase (AR), which catalyzes conversion of glucose to sorbitol (5). The key event is stimulation of transcription that is critically mediated by a cis element called tonicity-responsive enhancer (TonE). Each of the genes coding for SMIT (6), BGT1 (7), and AR (8) is regulated by multiple TonE present upstream of the promoter. TonE functions by providing a binding site for the transcription factor TonE binding protein (TonEBP) (9). In the N-terminus, TonEBP has a DNA binding domain that is similar to those of the transcription factor family NFAT. The C-terminus is rich in glutamine residues and likely is involved in stimulation of transcription.
The role of TonEBP in stimulation of transcription has been characterized extensively in MDCK cells, an epithelial cell line derived from the kidney. In this model, MDCK cells grown to monolayers in isotonic medium were switched to hypertonic medium, and changes in TonEBP and expression of its downstream genes SMIT, BGT1, and AR were studied. Earlier studies established that increased activity of TonEBP in the nuclei temporally correlates with binding of TonEBP in the TonE sites in situ and stimulation of transcription (10). More recent work with the use of specific polyclonal antibody to TonEBP demonstrated that activation of TonEBP is achieved by a combination of induction and localization of TonEBP into the nucleus (9,11). In isotonic conditions, TonEBP distributes equally in the nucleus and the cytoplasm. When cells are switched to hypertonic medium, redistribution of TonEBP into the nucleus becomes evident in 30 min and continues for several hours (12). Conversely, induction (an increase in whole-cell abundance) of TonEBP occurs over the course of 12 h and reaches a plateau of fourfold increase. The induction is due to an increase in synthesis of TonEBP as a result of increased abundance of mRNA (11). Inhibition of proteasome prevents the nuclear redistribution without affecting the abundance, resulting in blunted expression of downstream genes SMIT and BGT1 (13). Therefore, two independent pathways, induction and nuclear localization, are involved in stimulation of TonEBP in response to hypertonicity.
The goal of this study was to explore expression and regulation of TonEBP in rat kidneys in response to changes in water intake. Under these conditions, mRNA expression of the downstream genes of TonEBP, SMIT and AR, are known to be changed. The results demonstrate that changes in the nucleocytoplasmic distribution are the major mode of TonEBP regulation. Signals for the changes remain to be identified.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ribonuclease Protection Assays
Kidneys were perfused through the abdominal aorta with ice-cold
phosphate-buffered saline (PBS) to rinse out the blood. RNA was extracted from
the kidney cortex, outer medulla, and inner medulla using TriZOL (Life
Technologies, Grand Island, NY). A 430-bp rat SMIT cDNA corresponding to
nucleotides 490 to 919 of the canine cDNA
(14) was obtained from Dr.
Gorboulev (University of Wurzburg, Wurzburg, Germany). This fragment was
subcloned into pBluescriptII (Stratagen, La Jolla, CA), and antisense
riboprobe was synthesized using T7 RNA polymerase. A rat TonEBP cDNA
corresponding to nucleotides 4026 to 4319 of the human TonEBP cDNA
(9) was PCR-amplified from rat
genomic DNA. This fragment was cloned in pCRII-TOPO (Invitrogen, Carlsbad,
CA), and [32P]-labeled antisense probe was made with SP6 RNA
polymerase. The plasmid for synthesis of rat ß-actin probe was purchased
from Ambion (Austin, TX). Ribonuclease protection assay (RPA) was performed
using a commercial kit (Ambion). Radioactivity of SMIT and ß-actin bands
was quantified using Phosphoimager (Molecular Dynamics, Sunnyvale, CA). In
each reaction, SMIT or TonEBP mRNA was measured along with the ß-actin
mRNA, whose abundance was used to correct for RNA loading.
Immunoblot Analysis
The tissues were homogenized in modified RIPA buffer: 20 mM Tris-Cl (pH
7.5), 150 mM NaCl, 0.5% sodium deoxycholate, 1% Triton X-100, 0.1% sodium
dodecyl sulfate, 1 mM ethylenediaminetetraacetate and freshly added leupeptin
(5 µg/ml), and 1 mM phenylmethylsulfonyl fluoride. Homogenates were
centrifuged at 10,000 x g for 20 min at 4°C, and
supernatants were taken. Protein concentration was determined using the BCA
Protein Assay Reagent (Pierce, Rockford, IL) with bovine serum albumin (BSA)
as a standard. Samples were heated at 100°C for 5 min in Laemmli buffer,
separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in 8%
polyacrylamide gels and electroblotted onto Protran nitrocellulose transfer
membrane (Schleicher & Schuell, Keene, NH). The blots were blocked for 1 h
in 5% nonfat milk, 100 mM NaCl, 0.1% Tween-20, and 10 mM Tris-Cl (pH 7.5)
before incubation with 1:5000 dilution of the TonEBP antibody
(9) overnight at 4°C. The
blots were washed extensively in the Tris-buffered saline containing 0.1%
Tween 20 and incubated with 1:500 dilution of peroxidase-conjugated goat
anti-rabbit IgG Fab fragment (Jackson ImmunoResearch Laboratories, West Grove,
PA) for 2 h. Antibody-reactive protein was detected using enhanced
chemiluminescence (Amersham Life Sciences, Piscataway, NJ).
Preservation of Kidneys for Immunohistochemistry
The kidneys were preserved by in vivo perfusion through the
abdominal aorta. The animals were briefly perfused with PBS to rinse out the
blood. This was followed by perfusion with the
periodatelysine-paraformaldehyde (PLP) solution for 4 min. The kidneys were
removed and cut into sagittal slices of 1- to 2-mm thickness and postfixed
overnight in the PLP solution at 4°C. Fixed slices were cut along the
sagittal plane on Vibratome (Technical Products International, St. Louis, MO)
at a thickness of 50 µm and processed for immunohistochemistry.
Immunohistochemical Procedures
Fifty-micrometer Vibratome sections were processed for immunohistochemistry
using an indirect preembedding immunoperoxidase method. The sections were
washed three times for 15 min each in PBS containing 50 mM NH4Cl.
They were then incubated for 3 h in PBS containing 1% BSA, 0.05% saponin, and
0.2% gelatin (solution A). The tissue sections were incubated overnight at
4°C with the TonEBP antibody diluted 1:5000 in 1% BSA-PBS (solution B).
After several washes with solution A, the tissue sections were incubated for 2
h in a 1:50 dilution of peroxidase-conjugated goat anti-rabbit IgG Fab
fragment (Jackson ImmunoResearch Laboratories) in solution B. The tissues were
then rinsed, first in solution A and subsequently in 50 mM Tris-Cl (pH 7.6).
For the detection of horseradish peroxidase, the sections were incubated in
0.1% 3,3'-diaminobenzidine in the Tris buffer for 5 min. The reaction
was stopped with 0.01% H2O2 and washed in the Tris
buffer. The sections were dehydrated in a graded series of ethanol and
embedded in Epon-812. The embedded 50-µm thick sections were examined
before 2-µm thick sections were cut and photographed on an Olympus
Photomicroscope (Tokyo, Japan) equipped with differential-interference
contrast.
In Situ Hybridization
The PLP-fixed kidneys were embedded in wax, and 4-µm sections were
prepared. Digoxigenin-labeled antisense SMIT riboprobe was prepared using DIG
RNA Labeling Kit (Boehringer Mannheim, Indianapolis, IN) using the same
plasmid for RPA probe synthesis. Control sense probe was made using T3 RNA
polymerase. After dewaxing, the sections were treated in 0.2 N HCl for 30 min
at room temperature. The sections were rinsed with diethyl
pyrocarbonatetreated PBS and dehydrated with graded ethanol series and dried.
Prehybridization was performed for 2 h at 53°C in 50% formamide, 4x
SSC, 10% dextran sulfate, 1x Denhardt's solution, and 1 mg/ml salmon
sperm DNA. Hybridization was followed for 15 h in the same solution except
that salmon sperm DNA was substituted with digoxigenin-labeled SMIT riboprobe
(400 ng/ml). The sections were washed and incubated with anti-digoxigenin
antiserum conjugated with alkaline phosphatase, and histochemical detection
was then performed using nitroblue tetrazolium and 5-bromo-4-chloro-3-indolyl
phosphate (Boehringer Mannheim).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To measure changes in the activity of TonEBP, we measured mRNA expression of its target gene SMIT separately in the cortex, outer medulla, and inner medulla (Figure 1A) using RPA. In the inner medulla, the mRNA abundance doubled in dehydrated animals, whereas it halved in water-loaded animals. The changes were moderate in the outer medulla. These data suggest that dehydration increased the activity of TonEBP, whereas water loading decreased it.
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To investigate the mechanisms for the changes in TonEBP activity, we performed a number of experiments. Initially, TonEBP mRNA was quantified using RPA. The abundance of TonEBP mRNA in the inner and outer medulla was three to four times higher than the cortex (Figure 1B). There were no changes, however, in the mRNA abundance among the three groups of animals. Immunoblot analyses revealed that the inner and outer medulla express much more TonEBP than the cortex, where TonEBP expression sometimes was not visible (Figure 2). More important, there were no consistent changes in the abundance of TonEBP throughout the kidney (Figure 2). We conclude that overall abundance of TonEBP mRNA and protein is not affected by the water loading and dehydration protocols used in this study.
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Next, we performed immunohistochemistry to localize and to detect changes in TonEBP expression. Figure 3 shows a low-magnification view of TonEBP staining in a longitudinal section of a control kidney. The intensity of immunoreactivity was strongest in the inner medulla and the inner stripe of the outer medulla. Confirming the data presented above, there were no consistent differences in overall intensity of the staining among the three groups of animals (not shown). To examine TonEBP at the cellular level, we prepared thin (2 µm thick) sections and examined them under high power (Figures 4,5,6). Because changes in TonEBP staining were modest, sections from three to four animals were blindly examined and scored by three investigators. A summary is presented in Table 2.
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Figure 4 shows representative sections from control kidneys. In the cortex, the glomeruli were mostly negative except for weak staining in the podocytes and parietal epithelia. In the proximal tubules, a fraction of cells in the S1 and S2 segments (Figure 4A) and most cells in the S3 segment displayed weak staining in the nuclei. The strongest immunoreactivity in the cortex is in the cortical collecting ducts. The immunoreactivity also was evident in the distal convoluted tubules, connecting tubules, and cortical thick ascending limbs. In the outer stripe of the outer medulla, thick ascending limbs and collecting ducts showed strong staining. In the inner stripe of the outer medulla, the descending thin limbs stained far more intensely than any of other cell type (Figure 4B) in both the nuclei and the cytoplasm. The thick ascending limbs and collecting ducts also stained strongly. The thin limbs of the loops of Henle stained intensely throughout the inner medulla (Figure 4, C and D). In the collecting ducts, the immunoreactivity was weak at the initial portion of the inner medulla but dramatically stronger in the middle portion and even stronger in the terminal portion. The interstitial cells and blood vessels also stained more strongly in the inner medulla than in the cortex.
Figure 5, A and B, compares TonEBP immunoreactivity in the cortex from water-loaded and dehydrated rat kidneys, respectively. The immunoreactivity in the nuclei of connecting tubules generally was higher in the dehydrated animals compared with water-loaded animals. The same trend also was observed in the cortical collecting ducts, cortical thick ascending limbs, and S3 segments of the proximal tubules (Table 2).
In the inner stripe of the outer medulla (Figure 5, C and D), prominent changes occurred in the descending thin limbs of the loops of Henle. In the water-loaded animals, relative immunoreactivity of the nucleus over the cytoplasm varied widely: in some cells, nuclei stained more than the cytoplasm, whereas in other cells, the opposite held. However, in dehydrated animals, the nuclei invariably stained stronger than the cytoplasm. Elsewhere throughout the outer medulla, the immunoreactivity was higher in the nuclei of collecting ducts and thick ascending limbs of the dehydrated animals.
The most conspicuous changes were seen in the initial portion of the inner medulla (Figure 6, A and B). In the thin limbs of the loops of Henle from water-loaded animals, the majority of nuclei displayed weaker immunoreactivity, whereas the cytoplasm stained intensely. This was dramatically reversed in the dehydrated animals, in which the nuclei stained far more intensely than the cytoplasm.
Inner medullary collecting ducts showed different responses depending on the position along the inner medulla. In the initial portion, immunoreactivity in the nuclei was increased clearly in the dehydrated animals compared with the water-loaded animals. In Table 2, TonEBP was scored "±" in water-loaded and "+" in dehydrated animals. The changes were consistent even though they were small because of the low intensity of signal. In the middle and terminal portions of the inner medulla, however, most cells displayed intense nuclear immunoreactivity and we did not see consistent differences in the immunoreactivity between the two groups of animals (Figure 6, C and D).
In summary (Table 2), with exceptions of the collecting ducts in the middle and terminal portions of the inner medulla and blood vessels throughout, the nuclei of most cells in the medulla displayed stronger TonEBP immunoreactivity in the dehydrated animals compared with the water-loaded animals. It should be emphasized that the scores in Table 2 are conservative in that changes between different groups are indicated only when all three investigators agreed after blinded inspection of pictures. Regardless, these changes represent an increased distribution of the TonEBP in the nuclei over the cytoplasm because there are no changes in the overall abundance of TonEBP (Figure 2).
To localize the activity of TonEBP, we performed in situ hybridization using immunohistochemical techniques to detect SMIT mRNA. In control kidneys (not shown), staining for SMIT mRNA was most intense in the outer medulla. In this region, the thick ascending limbs stained strongest. Moderate staining also was present in the S3 segment of the proximal tubule, collecting duct, and thin limb of Henle. In the cortex, moderate staining was seen in the distal tubule, connecting segment, collecting duct, and parietal cells and podocytes of glomerulus. In the inner medulla, staining was weak in the initial portion, but staining intensified progressively along the middle and the terminal portions.
Figure 7 compares distribution of SMIT mRNA in kidneys from water-loaded and dehydrated rats. Most conspicuous changes occurred in the outer medulla: water loading (Figure 7A) led to a decrease in SMIT mRNA compared with controls (not shown), whereas dehydration (Figure 7B) led to a marked increase. Changes in SMIT mRNA expression also were evident in the initial portion of the inner medulla. Signals were very low in the renal tubules of the water-loaded rats (Figure 7, C and E), whereas strong signals were detected in dehydrated kidneys, especially in the thin limb of Henle's loop (Figure 7, D and F). In the middle to terminal portions of the inner medulla (Figure 7, G and H), however, almost all of the renal tubule cells showed the strong hybridization signals and there was no distinct difference between the water-loaded and dehydrated rats. Overall, differences in SMIT mRNA expression followed the nuclear distribution of TonEBP summarized in Table 2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite the changes in nuclear abundance of TonEBP, overall abundance of TonEBP in the renal medulla varied little (Figures 1B and 2). Studies in cultured kidney cells revealed that induction of TonEBP saturates at a tonicity of approximately 450 mOsm (11). In other words, the abundance of TonEBP does not increase further when tonicity of the culture medium is raised above 450 mOsm. The cells in the renal medulla seem to be responding in the same way as the cultured cells. In the outer medulla of kidneys from the Brattleboro rats producing hypotonic urine, the tonicity (non-urea component of total osmolality) of the interstitium is estimated to be above 500 mOsm (19). Under most water diuretic (e.g., without the use loop diuretics) and antidiuretic conditions, including those used in this study, changes in salt content in the outer and inner medulla of the kidney are relatively moderate (3,19,20). In fact, changes in urea concentration account for the majority of the change in osmolality of the interstitium. Therefore, the lack of change in overall abundance of TonEBP observed in this study very likely is due to the tonicity of the interstitium remaining above 500 mOsm throughout the renal medulla, well above the saturation point (450 mOsm) of TonEBP induction in cultured renal epithelial cells.
A key finding of this study is that shifts in the nucleocytoplasmic distribution rather than changes in abundance are the major mechanism of TonEBP regulation in the renal medulla in response to changes in water intake. This is most dramatic in the thin limbs, especially in the initial portion of the inner medulla. Signals for the shift in the nucleocytoplasmic distribution of TonEBP in the renal medulla are unknown. One obvious candidate is the change in tonicity of the interstitium even though it is moderate. The concentration of urea may be another candidate as it changes to a much greater extent than tonicity (see above). In cultured renal cells, raising osmolality of the medium by adding urea does not affect TonEBP (11). Nonetheless, it remains to be seen whether the same holds in the renal medulla.
Another notable finding is that in the middle to the terminal portions of the inner medulla, TonEBP distribution and SMIT expression do not vary appreciably in response to changes in water loading. A possible explanation is that the interstitial tonicity is higher than a set point beyond which tonicity no longer affects TonEBP. We are testing this using cultured cells.
Throughout the kidney, including the cortex, the level of TonEBP expression varies greatly within many areas of the same osmolality. In the cortex, where osmolality of the interstitium is isotonic, some cells and cell types do not express TonEBP whereas others, such as the cortical collecting ducts, express TonEBP vigorously. This is in contrast to cultured kidney cells, where practically every cell expresses TonEBP (9,11,12,13). In the outer medulla, the descending thin limbs of the loops of Henle express far more TonEBP than the thick ascending limbs (Figures 4 and 5) even though they are bathed in the same interstitium. The same holds for the thin limbs and collecting ducts in the initial portion of the inner medulla (Figures 4C and 6, A and B). Evidently, factors other than tonicity must be involved. Identification of these factors will help in identifying the signaling pathways to TonEBP.
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