1 Renal Unit and Department of Medicine, Massachusetts General Hospital, Charlestown 02129; 2 Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut 06519; and 3 Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge, Massachusetts 02139
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ABSTRACT |
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Kidney injury molecule-1 (Kim-1) is a
type 1 membrane protein maximally upregulated in proliferating and
dedifferentiated tubular cells after renal ischemia.
Because epithelial dedifferentiation, proliferation, and local
ischemia may play a role in the pathophysiology of autosomal
dominant polycystic kidney disease, we investigated Kim-1 expression in
a mouse model of this disease. In the Pkd2WS25/ mouse
model for autosomal dominant polycystic kidney disease, cystic kidneys
show markedly upregulated Kim-1 levels compared with noncystic control
kidneys. Kim-1 is present in a subset of cysts of different sizes and
segmental origins and in clusters of proximal tubules near cysts.
Kim-1-expressing tubular cells show decreased complexity and quantity
of basolateral staining for Na-K-ATPase. Other changes in polarity
characteristic of ischemic injury are not present in
Kim-1-expressing pericystic tubules. Polycystin-2 expression is
preserved in Kim-1-expressing tubules. The interstitium surrounding
Kim-1-expressing tubules shows high proliferative activity and staining
for smooth muscle
-actin, characteristic of myofibroblasts. Although
the functional role of the protein in cysts remains unknown, Kim-1
expression in tubules is strongly associated with partial
dedifferentiation of epithelial cells and may play a role in the
development of interstitial fibrosis.
Na-K-ATPase; cell polarity; fibrosis; Tim; ischemia; kidney obstruction
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INTRODUCTION |
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AUTOSOMAL DOMINANT POLYCYSTIC kidney disease (ADPKD) is the most commonly inherited monogenetic renal disease, affecting >1 in 1,000 live births. In the United States, it leads to end-stage renal disease in >1,500 patients/yr (24). In most patients, the disease is caused by an inherited defect in one of two polycystin genes, PKD1 or PKD2 (10a, 16). Random loss of heterozygosity in individual tubular epithelial cells is thought to be responsible for the transformation of epithelial cells through somatic inactivation of the second copy of the affected gene. The resulting dedifferentiation and proliferation causes progressive cyst formation (31). The PKD2 gene product polycystin-2 is a nonselective cation channel, and polycystin-1 may be required for its proper localization and function (8, 11, 13). The molecular mechanisms underlying the epithelial transformation are unknown. Epithelial cells in cysts have been shown to be dedifferentiated and to have increased proliferative indices (18, 21). The growth of cysts leading to massively enlarged kidneys is thought to be responsible for regional ischemia, which contributes to elevations in plasma renin and hypertension (5). Less than 1% of all nephrons are directly affected by cysts; therefore, direct nephron loss through cyst formation does not explain the decline of renal function. Progressive nephron loss is thought to involve apoptosis (30) and fibrosis (19) in areas adjacent to cysts, but this process is not very well characterized.
Kidney injury molecule-1 (Kim-1)1
is a type 1 transmembrane protein that is expressed at very low levels
in normal kidneys and is maximally upregulated in the S3 segment of the
proximal tubule 24-48 h after exposure of the kidney to transient
ischemia (12). It is expressed in human kidneys
with acute tubular necrosis and can be detected in the urine of these
patients (10). In the postischemic kidney,
Kim-1 is expressed in vimentin-positive cells and cells that take up
5-bromo-2'-deoxyuridine (12), suggesting a role for the
protein in the dedifferentiation and proliferation of epithelial
cells. Because epithelial dedifferentiation, proliferation, and
ischemia may play a role in the pathophysiology of ADPKD, we
examined the pattern of Kim-1 expression in cystic kidneys in the
Pkd2WS25/ mouse model. We found that Kim-1 is expressed
in polycystic kidneys but not in normal kidneys. Kim-1 expression is
found in a small subset of cysts of varying sizes and different
segmental origins. Additionally, we found a striking pattern of Kim-1
expression in clusters of noncystic tubules adjacent to cysts in
regions characterized by interstitial cell proliferation and fibrosis. In tubular cells, Kim-1 expression is associated with a decrease in
complexity and quantity of Na-K-ATPase expression, without other
features of loss of cell polarity, as reflected by actin, villin, and
E-cadherin staining patterns. The functional role of Kim-1 expression
in cysts is unclear. The tubular and peritubular findings support the
possibility that Kim-1 may play a role in interstitial fibrosis and
nephron loss in ADPKD.
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METHODS |
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Animals and tissues.
Pkd2WS25/ mice (31) and wild-type (WT)
littermates were genotyped by Southern blot analysis. Unilateral
ureteral obstruction and renal ischemia with reperfusion were
performed as previously described by our laboratory (20).
For total protein lysates, the kidneys were harvested unfixed and shock
frozen in liquid nitrogen. For immunohistochemical analysis, mice were
perfused via the left ventricle with paraformaldehyde-lysine-periodate solution containing 2% paraformaldehyde, 38 mM phosphate buffer, 60 mM
lysine, 10 nM sodium periodate, and 5% sucrose. Subsequently, kidneys were immersed in 2% paraformaldehyde for 4 h, washed in PBS, and cryoprotected by overnight submersion in 30% sucrose in 1×
PBS. Five-micrometer frozen sections were cut in a cryostat.
Antibodies.
Primary antibodies included the following. AKG7 is a mouse monoclonal
antibody against the extracellular domain of human KIM-1 (1a).
R9 is a rabbit polyclonal antibody, which was raised to the
intracellular domain of rat Kim-1 (see Fig. 1)
(12). Monoclonal anti-Na-K-ATPase 6F was obtained
from the Developmental Studies Hybridoma Bank (University of Iowa). It
recognizes the 1-subunit and has been well characterized
(1). Monoclonal anti-E-cadherin was purchased from BD
Transduction Laboratories. Mouse anti-PCNA was purchased from DAKO, and
mouse anti-smooth muscle
-actin is from Sigma. Polyclonal rabbit
anti-polycystin 2 YCC is a gift from Dr. Yiqiang Cai (Yale University
School of Medicine) (4). Polyclonal rabbit anti-villin and
rabbit anti-aquaporin-2 are gifts from Dr. Dennis Brown (Massachusetts
General Hospital) (2). Polyclonal rabbit anti-aquaporin-1
is a gift from Dr. Alfred Van Hoek (Massachusetts General Hospital)
(23). Secondary antibodies were Cy3-conjugated goat
anti-rabbit and FITC-conjugated goat anti-mouse (Sigma). Actin was
visualized by using tetramethylrhodamine isothiocyanate-labeled
phalloidin (Sigma).
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Apoptosis. TdT-mediated dUTP-X nick-end-labeling staining was performed with materials obtained from Boehringer according to instructions supplied by the manufacturer.
Subcloning. Expressed sequence tag (EST) AA547594 was identified by the Basic Local Alignment Search Tool (BLAST) to have significant sequence homologies to rat Kim-1 and was obtained from the IMAGE consortium (clone 960204) (14). After further sequencing, it was found to contain the full open reading frame of putative mouse Kim-1. Subcloning of the entire open reading frame was performed by PCR in pCR2.1 (Invitrogen), using primers 5'-CGCGTGGACCATGAATCAGATTC-3' and 5'-CTGCCCCTCAAGGTCTATCTTC-3'. Subsequently, the insert was subcloned into the EcoRI site of pCDNA3 (Invitrogen). The sequence was confirmed through double-stranded sequencing. Sequence analysis was performed with MacVector 6.5 software (Oxford Molecular).
Cell cultures and transient transfection. COS1 cells were maintained in DMEM supplemented by 10% fetal calf serum. Transient transfections were carried out with the superfect reagent (Qiagen) according to instructions by the manufacturer.
Proteins and Western blot. For SDS-PAGE, shock-frozen kidney tissue was homogenized in sample buffer containing 125 mM Tris, pH 6.8, 4.1% SDS, 20% glycerol, and 2% mercaptoethanol. Lysis of cells for protein analysis, electrophoresis, transfer, and Western blotting were performed as previously described (20).
Immunohistochemistry. Tissue sections were boiled in 0.1 M Na citrate buffer for 10 min, incubated with 1% SDS in PBS for 5 min, washed with 1× PBS, and blocked in 1× PBS with 2% FCS, 5% sucrose, and 0.1% IPEGAL CA-630 (Sigma). Incubation with primary antibody was done overnight at 4°C or for 1 h at room temperature. Secondary antibodies were applied for 1 h at room temperature. For immunofluorescence, slides were mounted with Vectashield (Vector Labs) in 1:1 dilution with 1.5 M Tris, pH 8.9, and examined under an epifluorescence microscope (Nikon Microphot FXA). Images were captured with a Hamamatsu Orca charge-coupled device camera and processed with IPLab Spectrum software (Scanalytics, Vienna, VA).
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RESULTS |
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Cloning of a mouse ortholog to rat Kim-1 and confirmation of
cross-reactivity of the anti-rat Kim-1 antibody R9 with mouse Kim-1.
With the purpose of studying Kim-1 expression in a mouse model of
ADPKD, we searched the database for mouse genes with homologies to
human KIM-1 and rat Kim-1. A putative mouse
ortholog of rat Kim-1 was identified by BLAST search of the mouse EST
database. EST AA547594 was found to contain the full coding region of putative mouse Kim-1 (mKim-1). Comparison of the
deduced amino acid sequence with rat Kim-1 shows 58% identity. There
is a high degree of homology in the protein region to which a rabbit
anti-rat-Kim-1 antibody, R9, had been raised (Fig.
1). Binding of R9 to mKim-1 was
demonstrated by Western blot analysis of total cell lysates of COS
cells transfected with the mKim-1 expression
construct (Fig. 2).
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Mouse Kim-1 is expressed in the
Pkd2WS25/ mouse model of ADPKD.
Expression of mouse Kim-1 is markedly increased in kidneys of
Pkd2WS25/
mice, compared with minimal basal expression in
kidneys from WT mice (Fig. 3). Kim-1
staining is present in 2-5% of cysts and can be seen in cysts
of different sizes (Fig.
4A). Two patterns of
Kim-1 expression are observed in Pkd2WS25/
kidneys.
One pattern of Kim-1 staining in cyst epithelia is apical (Fig.
4B), whereas the other is intracellular (Fig.
4C). In addition to Kim-1-staining cysts, occasional
clusters of Kim-1-staining noncystic tubules are seen in areas adjacent
to Kim-1-negative cysts (Fig. 4D). No staining for Kim-1 is
present in normal kidneys from WT mice.
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Kim-1-expressing cysts are derived from different segmental
origins.
Kim-1 expression after ischemia-reperfusion injury is
localized to the proximal tubule (12). To evaluate whether
Kim-1 expression occurs only in cysts of proximal tubular origin, we
examined Kim-1-expressing cysts for staining with the proximal tubular
marker aquaporin-1 and the collecting duct marker aquaporin-2. Some
Kim-1-positive cysts express aquaporin-1 (Fig.
5B) but not aquaporin-2 (Fig. 5C), whereas others stain for aquaporin-2 (Fig.
5F) but not aquaporin-1 (Fig. 5E). Some
Kim-1-positive cysts do not express either aquaporin-1 or aquaporin-2
(data not shown). These findings indicate that Kim-1 expression in
cysts is not related to their segmental origin.
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The staining pattern for Kim-1 differs between pericystic tubules and obstructed WT kidneys. In tubules adjacent to cysts, the staining pattern is apical and occasionally lateral (Fig. 5G). Staining for Kim-1 is often discontinuous, with only some of the epithelial cells in a given tubule expressing detectable amounts (Fig. 5H). Because it has been proposed that tubular obstruction plays a role in the pathophysiology of ADPKD (25), we compared the Kim-1 expression pattern in ADPKD to that observed in obstructed kidneys. We found Kim-1 uniformly expressed in all cells of a tubular segment 48 h after transient ureteral obstruction in WT mice (Fig. 5I), a pattern markedly different from the pattern of sporadic cell staining within a given tubule in cystic kidneys.
Kim-1-expressing tubular epithelial cells have decreased complexity
and quantity of Na-K-ATPase expression but maintain normal expression
of actin, villin, and E-cadherin.
Because Kim-1 is expressed in dedifferentiated epithelial cells after
ischemic injury (12), we analyzed Kim-1-expressing tubular cells for the distribution of Na-K-ATPase. Basolateral expression of Na-K-ATPase is a marker of terminal differentiation of
epithelial cells (28) and is decreased after
ischemic injury (33). In tubules adjacent to
cysts, single Kim-1-positive cells (Fig.
6, A and D) exhibit
a loss of complexity (Fig. 6E) and decreased quantity (Fig.
6, B, C, E, and F) of Na-K-ATPase expression,
whereas Kim-1-negative cells in the same tubule have a normal staining pattern for Na-K-ATPase. We additionally examined the staining pattern
of actin and villin, which have been shown to partially redistribute
from the apical brush border of epithelial cells to the basolateral
membrane after renal ischemia (2). A normal distribution of apical brush-border staining for actin (not shown) and
villin is present in Kim-1-expressing pericystic tubules (Fig. 6,
G and H). Because ischemia has been shown
to result in breakdown of the adherens junction and loss of lateral
E-cadherin expression in epithelial cells (3), we also
examined E-cadherin staining in Kim-1-expressing tubules. E-cadherin
staining is preserved in the lateral membrane of Kim-1-expressing cells
(Fig. 6, I-L). These results indicate that Kim-1
expression in epithelial cells is associated with a partial loss of
polarity. This is not likely to be due to ischemia.
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Different distribution patterns of Na-K-ATPase are found in
Kim-1-expressing cysts.
Because Kim-1-expressing tubular cells show alterations of
Na-K- ATPase expression that are consistent with a state of partial dedifferentiation and dedifferentiation of epithelial cells has been
implicated to play a role in cyst formation, we investigated the
staining pattern for Na-K-ATPase in Kim-1-expressing cysts. Cysts with
apical Kim-1 expression have preserved basolateral staining for
Na-K-ATPase (Fig. 7,
A-C), whereas cystic
epithelia with cytoplasmic Kim-1 expression show diffuse staining for
Na-K-ATPase (Fig. 7, D-F). Diffuse, as well as
basolateral, staining for Na-K-ATPase in cysts is also found in the
absence of Kim-1 expression. Lateral staining for E-cadherin is
preserved in all Kim-1-expressing cysts, as reflected in an example of
a Kim-1-positive cyst with diffuse expression of Na-K-ATPase (Fig. 7,
G-I). These findings of apical Kim-1 expression with
basolateral staining for Na-K-ATPase in cysts are different from the
findings in Kim-1-positive tubular cells, wherein the expression of
Kim-1 is associated with loss of quantity and complexity of basolateral
Na-K-ATPase staining.
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Kim-1-expressing tubular cells are surrounded by proliferating
cells and interstitial myofibroblasts.
Kim-1 is expressed in proliferating tubular epithelial cells after
ischemic injury (12). Because increased cell
proliferation has been observed in ADPKD (18, 21), we
examined cellular proliferation in Kim-1-expressing epithelial cells by
PCNA staining. We observed PCNA staining in only a few positive cells
that express Kim-1, either in cysts or in pericystic tubules (data not
shown), but found a greater number of PCNA-positive cells in the
peritubular interstitium surrounding Kim-1-expressing tubules (Fig.
8, A, C, and
E). Increased numbers of PCNA-positive cells were also found
in some non-Kim-1-expressing tubules in these same areas, consistent
with a "field effect," as previously described (18). In contrast, very few proliferating cells are found in the interstitial areas adjacent to Kim-1-negative tubules (Fig. 8, B,
D, and F).
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DISCUSSION |
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Despite important insights into the molecular genetics of ADPKD (24) and recent data about the function of the polycystins (8, 11, 13), the precise mechanism of cyst formation and the pathophysiology leading to interstitial fibrosis and nephron loss in ADPKD remain unknown. In this report, we demonstrate that Kim-1 is expressed in a subset of cysts, without a clear association with cyst size, segment of origin, or proliferative activity. Kim-1 expression in tubules is associated with a partial loss of polarity, as indicated by a loss of complexity and quantity of Na-K-ATPase expression, but preserved staining for actin, villin, and E-cadherin. These findings raise the possibility that Kim-1 plays a role in the dedifferentiation of epithelial cells. Hypothetically, this could explain Kim-1 expression in cysts. The close relationship between apical Kim-1 staining in tubules and disordered Na-K-ATPase expression is not found in cysts as might be expected if Kim-1 expression was tightly coupled to Na-K-ATPase expression. Our findings do not rule out a more complex relationship between Kim-1 and Na-K-ATPase expression in cysts or an effect of Kim-1 expression on the differentiation status of epithelial cells in cysts.
In addition to Kim-1 expression in cysts, we found a striking pattern of Kim-1-expressing noncystic tubules clustered near cysts. These express polycystin-2 by immunostaining (data not shown); hence, Kim-1-positive tubular cells are not characterized by loss of heterozygosity, which is associated with cyst formation in this model. Because Kim-1 expression in proximal tubules is most pronounced after ischemia (12), and ischemia has been proposed to play a role in the pathophysiology of ADPKD (5), we looked for evidence of ischemic injury in Kim-1-expressing pericystic tubular cells. Ischemia is associated with breakdown of the adherens junction and disruption of the apical brush-border actin and villin localization pattern (2, 3). Our findings of normal distribution patterns for E-cadherin, actin, and villin make it very unlikely that tubular Kim-1 expression near cysts is a consequence of ischemic injury.
Tubular obstruction has also been proposed to play a role in progressive nephron loss in ADPKD (25). We found that obstructed kidneys express Kim-1. However, the expression pattern of Kim-1 in postobstructed kidneys is markedly different from the pattern in ADPKD. In postobstructed kidneys, Kim-1 is expressed in entire tubular segments, involving all cells of a given tubule, as opposed to the intermittent epithelial cell staining pattern in cystic kidneys. It is therefore unlikely that Kim-1 expression in pericystic tubules in ADPKD is a consequence of tubular obstruction.
The large number of PCNA-positive cells in the interstitium surrounding
Kim-1-expressing tubules together with the presence of smooth muscle
-actin-positive cells suggests that Kim-1 expression in proximal
tubules adjacent to cysts is associated with interstitial proliferation
and fibrosis. This is particularly important because the loss of renal
function in patients with ADPKD is not believed to be due solely to the
cysts themselves. Interstitial fibrosis and inflammation have been
implicated in nephron loss (32). It is possible that
pericystic Kim-1 expression in ADPKD kidneys is a consequence of
epithelial injury caused by a proliferative and fibrogenic interstitial
process. Alternatively, Kim-1 expression in tubular epithelial cells
could be a primary event leading to interstitial fibrosis. Proximal
tubular cells have been previously invoked in the pathogenesis of
tubulointerstitial damage and fibrosis in various animal models of
chronic renal disease, such as systemic lupus erythematosus
(26), diabetic nephropathy (29), and ureteral obstruction (27), and in studies of human tissues from
patients with chronic renal disease (9). The mechanisms
resulting in interstitial fibrosis are not understood, but chemokine
expression, such as monocyte chemoattractant protein-1, by tubular
epithelial cells has been implicated in the recruitment of interstitial
macrophages and the development of interstitial fibrosis (26,
27). Recent data from our laboratory that the extracellular
portion of Kim-1 is shed from the cell (1a) raise the possibility that
shed Kim-1 reaches the interstitium and plays a role in the appearance
of myofibroblasts and the proliferative and fibrogenic response. Further support for the concept that Kim-1 is an immunologically active
molecule comes from recently published evidence that suggests that
molecules of the Kim family are involved in T cell differentiation and
macrophage activation (15, 17).
In summary, we demonstrate that Kim-1 is expressed in murine ADPKD but not in normal kidneys. It is expressed in a small number of cysts and in a pattern of proximal tubule clusters adjacent to cysts. Kim-1 expression in single tubule cells is associated with a partial loss of polarity, which is likely unrelated to ischemic injury. Kim-1-expressing tubules are surrounded by a highly proliferative and fibrogenic interstitial response. In conclusion, we propose that Kim-1 expression may play a pathogenic role in the development of interstitial fibrosis and subsequent nephron loss in ADPKD.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Sayoko Nishimura and Xin Tian for assistance
with the Pkd2WS25/ mice. We thank Dr. Dennis Brown for
helpful discussions.
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FOOTNOTES |
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E. W. Kuehn was supported by Deutsche Forschungsgemeinschaft Grant DFG-Ku 1322/1-1 and the National Kidney Foundation. S. Somlo was supported by National Institutes of Health (NIH) Grants DK-54053 and DK-57328. J. V. Bonventre was supported by NIH Grants DK-39773, DK-38452, DK-46267, and NS-10828. The core facility used for the immunohistochemistry was partially supported by the Center for the Study of Inflammatory Bowell Disease Grant DK-43351.
Address for reprint requests and other correspondence: J. V. Bonventre, Massachusetts General Hospital East, Renal Unit 4th floor, Rm. 4002, 149 13th St., Charlestown, MA 02129 (E-mail: joseph_bonventre{at}hms.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 In Ref. 12, rat KIM-1 was capitalized. We have modified the nomenclature and reserved the capitalized form for human KIM-1. We refer to the rodent rat or mouse form as Kim-1 throughout this manuscript.
July 24, 2002;10.1152/ajprenal.00166.2002
Received 30 April 2002; accepted in final form 12 July 2002.
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