* Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University System Health Science Center; and Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University
Received March 2, 2004; accepted April 1, 2004
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ABSTRACT |
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Key Words: cadherin; catenin; mercury; nephrotoxicity.
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INTRODUCTION |
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The cadherin gene superfamily encodes for transmembrane proteins that regulate Ca++-dependent, homotypic intercellular adhesion. Type-I (classical) cadherins comprise a large family of highly homologous proteins, which includes E-(epithelial [L-CAM, uvomorulin]) N-(neuronal [A-CAM]), and P-(placental) cadherin (Kemler, 1992). The extracellular domain contains four highly conserved Ca++-binding "cadherin repeats" (EC14) and one membrane-proximal extracellular domain (EC5). Type-II (atypical) cadherins have a similar structure, but lack the conserved His-Ala-Val (HAV) sequence in the EC1 domain. Catenins, intracellular proteins that bind cadherins, are required for a functional intercellular adhesion complex.
-Catenin is linked to the cytoplasmic domain of cadherins via ß- or
-catenin; it does not directly bind to cadherin. Due to homology with vinculin, it is suggested that
-catenin links the cadherin/catenin complex to the cytoskeleton (Nagafuchi et al., 1991
). p120-Catenin binds to the cadherin cytoplasmic domain and shares sequence homology with ß- and
-catenin but does not bind
-catenin (Reynolds et al., 1994
).
The renal expression of cadherin molecules is complex, with reports of at least nine cadherins present in the kidney (E-, K-, Ksp-, N-, P-, R-, and T-cadherin; µ- and LKC protocadherins) (Cho et al., 1998; Dahl et al., 2002
; Goldberg et al., 2002
; Nouwen et al., 1993
; Okazaki et al., 2002
; Piepenhagen et al., 1995
; Thomson et al., 1995
). In addition to the developmental regulation of cadherin expression, evidence is accumulating that cadherin/catenin proteins are differentially expressed along the nephron. In the developing human kidney, N-cadherin is expressed in the proximal tubule and thin limb and E-cadherin is expressed in the thin limb, distal tubule and collecting tubule (Nouwen et al, 1993
). In the mouse embryonic kidney, the proximal tubule progenitors express K-cadherin (a type-II cadherin), while the distal tubule cells express E-cadherin and the glomeruli express P-cadherin. Ultimately, K-cadherin is downregulated during maturation whereas E-cadherin expression remains in most, if not all, of the tubular epithelium (Cho et al., 1998
). K-cadherin exhibits low homology to N-(38%), E-(35%), and P-cadherin (32%). It is expressed at high levels in fetal human kidney, and at low levels in adult kidney. In adult mouse kidney, E-cadherin is detected everywhere but the initial segment where the proximal tubule joins Bowman's capsule (Piepenhagen et al., 1995
). This pattern of expression contrasts with adult human kidney, where E-cadherin is not detected in the proximal tubule (Nouwen et al, 1993
).
- and ß-Catenin are expressed in all nephron segments, while
-catenin is only detected in distal tubules (Piepenhagen and Nelson, 1995
). Recently, a novel 130-kDa, kidney-specific member of the cadherin superfamily (Ksp-cadherin) was identified. Although Ksp-cadherin lacks the HAV adhesion recognition sequence and possesses a truncated cytoplasmic domain that does not interact with catenins, it is capable of mediating intercellular adhesion (Thomson et al., 1995
).
A rationale for studying the cadherin/catenin complex in mercuric chloride-induced acute renal failure (ARF) is the finding that a decrease in glomerular-filtration rate, as assessed by 3H-inulin clearance, was seen at the late proximal tubule but not at the Bowman's space in mercuric chloride-induced nephrotoxicity (Conger and Falk, 1986). This observation leds the authors to conclude "at 24 h in low-dose HgCl2-induced acute renal failure, tubular fluid back-leak is the major pathogenic factor." This suggests that disruption of intercellular adhesion, as evidenced by glomerular filtrate back-leak, is an important component of mercuric chloride-induced ARF in animal models, as well as human patients with ARF (Moran and Myers, 1985
; Myers et al., 1979
). The present study was designed to examine the expression and integrity of renal cadherin/catenin complexes in normal mouse kidney and during mercuric chloride-induced nephrotoxicity.
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MATERIALS AND METHODS |
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Animals. All animal protocols were approved by the Texas A&M University ULAC Committee (AUP 2001268). Male C3H mice (2025 g; Charles River) were maintained in the College of Medicine animal-care facility; this mouse strain was used based on the sensitivity of these animals to mercuric chloride (Tanaka-Kagawa et al., 1998). The animal room was temperature-controlled and on a 12/12 h light/dark cycle. Mice were given food and water ad libitum. Mice were injected with mercuric chloride (025 µmol/kg dissolved in PBS, total injection volume 250 µl, ip). Following anesthesia (isoflurane), the abdominal cavity was opened, and the kidneys were removed and weighed. The kidney capsule was removed and the kidneys sectioned (4 sagittal sections) and processed for analysis, as described below.
Western blots. Kidney samples were homogenized in 500 µl of lysis buffer (10 mM Tris/HCl, pH 7.6, 1% SDS; 1 mM PMSF; 1 mM leupeptin; 1 mM orthovandate) and boiled for 10 min. The homogenates were spun at 14,000 rpm for 10 min, and the supernatant was collected. Proteins were quantified by the Bradford method and diluted to 1 µg/µl in 2X sample buffer (250 mM Tris/HCl, pH 6.8, 4% SDS, 10% glycerol, 2% ß-mercaptoethanol, 0.006% bromphenol blue). Samples were boiled for 5 min prior to electrophoresis and protein was separated by 6% SDSPAGE. Separated proteins were transferred onto a Hybond-ECL nitrocellulose membrane (Amersham) in transfer buffer containing 25 mM Tris, 200 mM glycine, 20% methanol, and 1% SDS. Nonspecific binding was blocked by incubation with TBST blocking buffer (0.1% Tween-20, 10 mM Tris, pH 7.5, 100 mM NaCl) supplemented with 5% nonfat dry milk for 1 h at room temperature. Primary antibodies (Table 1) were diluted in the same buffer and incubated at 4°C overnight. After subsequent washes with TBST, membranes were incubated with secondary antibody (1:20,000 TBST:5% nonfat dry milk) against the appropriate species for 1 h at room temperature. The blots were washed 3X in TBST and proteins detected with the Amersham ECL system and exposure to X-ray film (Kodak, Rochester, NY) prior to scanning and analysis via the UN-SCAN-IT program (Silk Scientific, Orem, UT).
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Immunofluorescence. Kidney sections were immediately frozen in Tissue-Tek OCT compound (Miles Scientific) in a liquid nitrogen bath. All tissues were stored at 80°C until use. Samples were cut on a cryostat and 8 µm sections collected on slides (Permafrost Plus), fixed in 20°C methanol for 10 min, and then air dried. Sections were treated with 1:20 blocking solutions (serum related to species in which the secondary antibody was generated) at room temperature for 1 h. Primary antibodies were added at appropriate dilutions (Table 1) overnight at 4°C. After washing (0.3% Tween in 0.02 M PBS; PBST), FITC-conjugated secondary antibodies (1:200) were added and sections incubated in the dark at room temperature for 1 h. Sections were mounted with anti-fade media (Molecular Probes) following several washes. Immunostained sections were visualized with a Zeiss Axioplan 2 microscope (Carl Zeiss) fitted with a Hamamatsu chilled 3CCD color camera (Hamamatsu Corporation, Bridgewater, NJ) and images captured with Adobe Photoshop 5.0 software (Adobe Systems, Seattle, WA). Negative controls included both substituting appropriate species IgG for primary antibodies and substituting appropriate species serum for secondary antibodies in the staining reactions. On the basis of previously published studies (Piepenhagen and Nelson, 1995), we identified proximal tubules as
-catenin-negative.
Coimmunofluorescence. Following a 1-hr room temperature incubation in serum (1:20) related to species in which the secondary antibody was generated, 100 µl of primary antibody (1:100) was placed on each slide at 4°C, overnight. The slides were washed with PBST prior to 1-hr room temperature incubation with a secondary antibody coupled to FITC (1:200). The slides were again washed with PBST, and then blocked (serum related to species in which both the first and second secondary antibodies were generated) at room temperature for 1 hr. One hundred µl of primary antibody (1:100) was placed on each slide at room temperature for 1 h. Following washing, 100 µl of secondary antibody coupled to Texas Red (1:200) was incubated with each section at room temperature for 1 h. Sections were mounted with anti-fade media (Molecular Probes) following several washes. Immunostained sections were visualized using a Zeiss Axioplan 2 microscope, as described previously. Adobe Photoshop software was used to capture and merge individual FITC and Texas Red images.
Dual staining: Serial sections. For cases in which two antibodies were derived from the same source (i.e., two monoclonal antibodies; E- and N-cadherin), serial sections were used. The first and second sections were incubated with single monoclonal antibodies, and the third section was incubated with the monoclonal antibody used on the first section, each for 1 h. After washing with PBST, FITC-conjugated sheep antimouse IgG secondary antibody was incubated with first and third sections, while Texas red goat anti-mouse IgG secondary antibody was incubated with the second section. Following a second block, the third section was also incubated with a second primary antibody, followed by a Texas red goat antimouse IgG secondary antibody. Sections were mounted with antifade media (Molecular Probes) following several washes. Immunostained sections were visualized and images captured as described previously.
Immunoprecipitation. Kidney tissues were homogenized in 500 µl of lysis buffer (2% NP-40 in PBS; 1 mM PMSF, 1 mM leupeptin; 1 mM orthovandate). The samples were centrifuged for 15 min at 12,000 rpm (4°C). The supernatant was collected and incubated on a rocker platform for 30 min at 4°C with 50 µl of GammaBindTM Plus SepharoseTM; at 4°C, on a rocker platform. The samples were spun for 10 min at 12,000 rpm (4°C) and protein concentration determined using the Bradford assay. Five hundred µg of protein was incubated with 5 µg of antibody (TABLE 1) at 4°C for 1.5 h. GammaBindTM Plus SepharoseTM (25 µl) was added and the samples incubated at 4°C overnight. The proteins were collected by centrifugation for 10 min at 12,000 rpm at 4°C. The pellet was washed three times with lysis buffer prior to Western-blot analysis.
Renal function. Blood urea nitrogen (BUN) was assessed in collected blood samples using a commercially available kit (Sigma). Ten µl serum was added to a tube and incubated in 37°C water bath for 10 min. At this time, 1 µl phenol nitroprusside solution, 1 ml alkaline hypochlorite solution, and 5 ml H2O were added to each tube. The reaction was allowed to develop at room temperature for 30 min prior to spectrophotometric analysis.
Creatinine was also assessed with commercially available kits (Sigma). Three hundred µl of sample were added to a cuvette. To all cuvettes, 3 ml of alkaline picrate solution was added and incubated at room temperature for 10 min. Absorbance was read at 500 nm. After measurement, 0.1 ml acid reagent was added and the sample was incubated for 5 min at room temperature. Absorbance was then read again at 500 nm; the difference in absorbance before and after acidification correlates with the amount of creatinine.
Statistics. Data are expressed as mean ± SEM. An analysis of variance (ANOVA) was performed and a Dunnett's test was used to assess significant differences from the control group (p < 0.05).
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RESULTS |
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In the next series of experiments, the spatial expression of cadherins and catenins was examined by immunohistochemistry in paraformaldehyde-fixed, paraffin-embedded sections. N-cadherin and p120-catenin were detected only in proximal tubules, while Ksp-cadherin was detected in both proximal and distal tubules (data not shown). E- and K-cadherin and -, ß, and
-catenin were not detected with this strategy. Although these data demonstrated a distinct pattern of cadherin and catenin expression along the nephron, the inability to detect all of the cadherins and catenins in fixed, paraffin-embedded tissue necessitated development of an alternative strategy.
A coimmunofluorescence strategy using frozen tissue sections was employed to optimize antigen preservation and simultaneously detect two proteins. The colocalization of E- and N-cadherin is shown in Figure 1. The staining of N-cadherin was confined to the proximal tubules (Fig. 1A), while E-cadherin was expressed in both proximal and distal tubules; however, the intensity of the staining was greater in the distal segments (Fig. 1B). When the two images are merged, the colocalization of N- and E-cadherin in proximal tubules is evident, but not in the distal tubules (Fig. 1C). The specificity of the staining was demonstrated by the lack of a signal in the presence of sheep (Fig. 1D) or goat serum (Figs. 1E merged in 1F), or mouse IgG (Figs. 1G and 1H, merged in 1I) as controls for secondary and primary antibodies, respectively.
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DISCUSSION |
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We also extend the understanding of cadherin/catenin complexes by examining the colocalization and interaction of cadherins and catenins in the mouse kidney. The colocalization and coimmunoprecipitation studies yielded very similar results. N- and E-cadherin colocalized in proximal, but not distal tubules. Both - and ß-catenin colocalized with N-cadherin in proximal tubules, while no colocalization was seen between
-catenin and N-cadherin. E-cadherin was shown to colocalize with all of the catenins;
-, ß- and p120-catenin in proximal tubules and
-, ß-, and
-catenin in distal tubules. N-cadherin/ß-catenin/
-catenin co-immunoprecipitated, while
- and p120-catenin did not co-immunoprecipitate N-cadherin. As expected, based on colocalization, all catenins co-immunoprecipitated with E-cadherin. We conclude that in the proximal tubule, two distinct cadherin/catenin complexes exist: N-cadherin/ß-catenin/
-catenin and E-cadherin/ß-catenin/
-catenin/p120-catenin. In the distal tubule, E-cadherin/ß-catenin/
-catenin and E-cadherin/
-catenin/
-catenin complexes are present. These data are the first to define the spatial colocalization and co-immunoprecipitation patterns of renal cadherin and catenin complexes along the nephron.
K-cadherin is expressed in renal tubules (Cho et al., 1998; Shimazui et al., 2000
), but was not detected in C3H mouse kidney, either by immuno-histochemistry or by immunofluorescence using antirabbit (from Dr. Gregory Dressler), and antigoat (Santa Cruz Biotechnology) polyclonal antibodies. One explanation is that K-cadherin is highly expressed during renal development and is then downregulated, thereby accounting for its low expression level in adult mouse kidney. As K-cadherin expression is downregulated, E-cadherin becomes more prominent in the mature tubules (Cho et al., 1998
). However, faint bands were detected by Western blot. The function of p120-catenin is unclear and, most likely, cell-specific (Golenhofen and Drenckhahn, 2000). It is hypothesized that the cadherin/p120 complex is required for initial homotypic recognition, while ß- and
-catenin stabilize the cluster and strengthen cellcell adhesion via interaction with the actin cytoskeleton. The finding that cadherin proteins lacking the p120-catenin-binding site do not mediate receptor clustering in vitro (Thoreson et al., 2000
) supports this hypothesis. However, recent studies suggest that p120-catenin is not required for intercellular adhesion (Myster et al., 2003
; Pacquelet et al., 2003
) and that p120-catenin may inhibit cadherin-mediated adhesion in certain cell types (Aono et al., 1999
). In the present study we demonstrated that p120 was localized in proximal tubules by immunohistochemistry and immunofluorescence but results of immunofluorescent colocalization were equivocal. However, immunoprecipitation studies demonstrated that p120-catenin complexes with ß-catenin and E-cadherin, but not with
-catenin and N-cadherin. The most plausible explanation for this is that p120-catenin in proximal tubules complexes only with E-cadherin. These data raise the intriguing question of the function of p120-catenin in the proximal tubule.
We demonstrate that mercuric chloride-induced nephrotoxicty is (1) associated with a selective loss of expression of adhesion proteins in the kidney during the late stages of injury (1224 h), and (2) discrete alterations in cadherin/catenin intracellular localization and association occur prior to cell death (6 h). Based on the pattern of localization and coimmunoprecipitation, it is suggested that the selective protein loss cannot be accounted for solely by proximal tubular epithelial cell death. Prior to cell death (6 h) delocalization, loss of protein expression, and decreased protein:protein interactions in the N-cadherin/ß-catenin/-catenin complex was observed. These data suggest that the early stages of renal injury may be associated with disruption of intercellular adhesion. The changes in the cadherin/catenin complex are not specific for mercuric chloride. Similar changes in protein expression and localization were seen in mice challenged with 20 mg/kg cisplatin (data not shown), a nephrotoxic compound (Megeyesi et al., 1998
; Ramesh and Reeves, 2002
). The mechanism(s) underlying the loss of complex integrity during the early stages of ARF, and protein loss during the late stages of ARF are currently under investigation. An important area of future investigation will be to understand the relationship between disruption of the cadherin/catenin complex and tight junctions. Although no impact of mercuric chloride on the protein expression of occludin and ZO-1 was seen at 24 h, a loss of ZO-2 was seen (data not shown). Importantly, the relationship between both the delocalization and loss of
-catenin and tight junction integrity is under investigation, as a clear relationship between
-catenin and tight junctions has been demonstrated (Itoh et al., 1997
, 1999
).
An important aspect of these studies was the association between disruption of cadherin/catenin complexes and alterations in the localization of the 1 subunit of Na+/K+-ATPase. At the same time, the integrity of cadherin/catenin complexes was disrupted; a redistribution of
1 staining to the lateral membrane was seen, as well as a decreased intensity of staining on basal membranes. While these data suggest that cell polarity may be altered, a number of important questions remain including whether the disruption of the cadherin/catenin complex by nephrotoxicants is a direct effect, or is indirect as a result of alterations in other important structural components, particularly the actin cytoskeleton. In addition, mercuric chloride has been shown to bind (Bhattacharya et al., 1997
) Na+/K+-ATPase and disrupt membrane anchoring of this complex (Imesch et al., 1992
). Given that recent data suggests that Na+/K+-ATPase activity is necessary to establish polarity (Rajasekaran et al., 2001
), the alterations in cadherin/catenin complexes could be downstream from changes in the Na+/K+-ATPase.
In vivo evidence for disruption of cellcell adhesion during renal injury in animal models is lacking, although some evidence suggests that it may be associated with renal injury. Bush et al. (2000) have shown that ischemia caused a loss of cell-surface E-cadherin, and degradation of E-cadherin to an approximate 80 kDa fragment, suggesting that disruption of the cadherin/catenin complex in the kidney may represent a critical event in ischemia-induced renal injury. In addition, bismuth, a nephrotoxic metal, was shown to specifically alter the cellular localization of N-, but not E-, cadherin in the mouse proximal tubular epithelium (Leussink et al., 2001
). No changes in tight junction constituents were seen. These changes in the N-cadherin/catenin complex, in the absence of changes in E-cadherin and tight junctions are similar to our data using mercuric chloride-induced renal injury. Prozialeck and coworkers (2003)
have recently extended their in vitro studies (reviewed in Prozialeck, 2000
) investigating cadmium-induced disruption of cadherin/catenin complexes in the kidney. Specific changes in the localization of E- and N-cadherin and ß-catenin were observed in the proximal tubules of rats following subchronic challenge with cadmium chloride.
While evidence suggests that disruption of cellcell adhesion is associated with renal failure in patients; understanding of the cause and effect of this relationship is limited by the lack of in vivo studies. It is clear that a number of toxic insults (metals, ischemia, toxins, etc.) disrupt cellcell contacts in vitro, however, the in vivo relevance of these findings is uncertain. Many of the in vitro studies have focused on E-cadherin, despite the fact that expression of this cadherin is mostly limited to distal tubules. The large gap between our understanding of cell adhesion complexes and the role that disruption of homotypic cell adhesion may play in renal injury requires further investigation. However, the current studies demonstrate that ARF is associated with disruption of cadherin/catenin complexes at multiple levels: expression, localization, and interaction. These findings provide a basis for future investigations of the mechanism(s) involved in complex disruption during ARF, as well as the potential causal role of cadherin/catenin complexes in functional changes associated with renal pathophysiology.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at the Department of Medical Pharmacology and Toxicology, College of Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114. Fax: (979) 845-0699. E-mail: parrish{at}medicine.tamu.edu.
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