ARTICLE

Expression of the Membrane-associated Carbonic Anhydrase Isozyme XII in the Human Kidney and Renal Tumors

Correspondence to: Seppo Parkkila, Dept. of Anatomy and Cell Biology, Box 5000, FIN-90014 University of Oulu, Finland. E-mail: seppo.parkkila@oulu.fi

	Summary

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Carbonic anhydrase isozyme XII (CA XII) is a novel membrane-associated protein with a potential role in von Hippel–Lindau carcinogenesis. Although Northern blotting has revealed positive signal for CA XII in normal human kidney, this is the first study to demonstrate its cellular and subcellular localization along the human nephron and collecting duct. Immunohistochemistry with a polyclonal antibody (PAb) raised against truncated CA XII revealed distinct staining in the basolateral plasma membrane of the epithelial cells in the thick ascending limb of Henle and distal convoluted tubules, and in the principal cells of the collecting ducts. A weak basolateral signal was also detected in the epithelium of the proximal convoluted tubules. In addition to the normal kidney specimens, this immunohistochemical study included 31 renal tumors. CA XII showed moderate or strong plasma membrane-associated expression in most oncocytomas and clear-cell carcinomas. The segmental, cellular, and subcellular distribution of CA XII along the human nephron and collecting duct suggests that it may be one of the key enzymes involved in normal renal physiology, particularly in the regulation of water homeostasis. High expression of CA XII in some renal carcinomas may contribute to its role in von Hippel–Lindau carcinogenesis.

(J Histochem Cytochem 48:1601–1608, 2000)

Key Words: aquaporin-2, cancer, carbonic anhydrase, carcinoma, immunohistochemistry, kidney, plasma membrane

	Introduction

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THE HISTOLOGICAL LOCALIZATION of CA activity has been extensively studied in kidney (Lonnerholm 1973 , Lonnerholm 1983 ; Lonnerholm and Ridderstrale 1974 , Lonnerholm and Ridderstrale 1980 ; Lonnerholm and Wistrand 1984 ). However, these studies have not provided much information about the differential expression of CA isozymes in the nephron and collecting duct. When CA isozyme-specific antibodies became available, they were rapidly adopted for immunolocalization studies of kidney specimens. For the first time, these antibodies enabled researchers to compare the distributions of CA I, II, and III in kidney and various other sites (Spicer et al. 1979 , Spicer et al. 1982 , Spicer et al. 1990 ). The intercalated cells of the late distal tubule, the collecting tubule, and the collecting duct were found to express high levels of CA II (Sato and Spicer 1982 ; Brown et al. 1983 ; Lonnerholm and Wistrand 1984 ; Brown and Kumpulainen 1985 ; Spicer and Schulte 1990 ). In addition, some immunoreaction was observed in the loop of Henle (Spicer et al. 1982 ; Lonnerholm et al. 1986 ), the proximal tubules (Spicer et al. 1982 , Spicer et al. 1990 ; Lonnerholm et al. 1986 ), and the principal cells of the collecting ducts (Holthofer et al. 1987 ). The physiological importance of renal CA II was documented when Sly et al. 1983 , Sly et al. 1985 reported renal tubule acidosis in patients with human CA II-deficiency syndrome.

Membrane-associated CA IV is expressed on the apical brush-border membrane of the rat proximal tubule cells (less on the basolateral membrane) and on the cells of the thick ascending limbs of Henle (Brown et al. 1990 ). The physiological role of CA IV in the kidney is to facilitate bicarbonate reabsorption by catalyzing its dehydration to carbon dioxide (Sly and Hu 1995 ). After entering the epithelial cell by diffusion, carbon dioxide is available for CA II-catalyzed hydration, to generate protons for luminal acidification.

The reports on a novel membrane-associated isozyme, CA XII, have raised considerable interest because its mRNA is expressed in the normal human kidney and overexpressed in some malignant cells, including non-small-cell lung carcinoma cells and renal cancer cells (Ivanov et al. 1998 ; Tureci et al. 1998 ). Interestingly, Ivanov et al. 1998 demonstrated that the CA12 gene expression is downregulated by the product of the wild-type von Hippel–Lindau tumor suppressor gene (pVHL). The above findings prompted Ivanov et al. 1998 to suggest that CA XII might serve as a useful biomarker for some malignant tumors and might also be considered a potential target for novel therapeutic applications.

Immunohistochemistry for CA XII has recently been reported in the human endometrium (Karhumaa et al. 2000a ) and colon (Kivela et al. 2000 ), in which the enzyme was confined to the basolateral plasma membrane of the epithelial cells. The present study was designed to examine the immunohistochemical distribution of CA XII in normal human kidney and in renal neoplasms. The new information on the expression of CA XII could help us to understand its physiological role in the normal kidney and to assess its role as a potential biomarker for renal tumors.

	Materials and Methods

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Antibodies
The anti-human CA XII antiserum to the secretory form of human CA XII was raised in rabbits as described earlier for CA IV (Zhu and Sly 1990 ; Parkkila et al. 1996 ). The antibody has been characterized recently by Karhumaa et al. 2000a . Polyclonal guinea pig antiserum against human CA II has been produced and characterized previously (Juvonen et al. 1994 ). Aquaporin-2 (AQP2) antibodies raised against peptides mapping at the carboxy (C-17) or amino (N-20) terminus of the protein were purchased from Santa Cruz Biotechnology (Santa Cruz, CA).

Immunocytochemistry
Samples of normal human kidney (n = 4) and renal neoplasms (n = 31) were obtained together with routine histopathological specimens taken during surgical operations for renal carcinoma. The renal tumor specimens included 16 clear-cell carcinomas (grade 1, n = 4; grade 2, n = 2; grade 3, n = 7; grade 4, n = 3), two chromophilic carcinomas, two chromophobic carcinomas, five oncocytomas, one angiomyolipoma, and five Wilms' tumors. The procedures had the approval of the ethics committee of Oulu University Hospital and the research was carried out according to the provisions of the Helsinki Declaration of 1975. Each tissue sample was divided into several small pieces about 5 mm thick. The specimens were fixed in Carnoy's fluid (absolute ethanol + chloroform + glacial acetic acid 6:3:1) for 6 hr at 4C or in 4% neutral-buffered formaldehyde for 24–48 hr at room temperature (RT). The samples were then dehydrated, embedded in paraffin in a vacuum oven at 58C, and sections of 5 µm were placed on gelatin-coated microscope slides. The immunostaining of tissue sections was performed using the biotin–streptavidin complex method, employing the following steps: (a) pretreatment of the sections with undiluted cow colostral whey for 40 min and rinsing in PBS; (b) incubation for 1 hr with the anti-human CA XII serum or nonimmune rabbit serum diluted 1:100 or 1:500 in PBS containing 1% bovine serum albumin (BSA); (c) treatment with cow colostral whey for 40 min and rinsing in PBS; (d) incubation for 1 hr with biotinylated swine anti-rabbit IgG (Dakopatts; Glostrup, Denmark) diluted 1:300 in 1% BSA–PBS; (e) incubation for 30 min with peroxidase-conjugated streptavidin (Dakopatts) diluted 1:500 in PBS; and (f) incubation for 2 min in DAB solution containing 9 mg 3,3'-diaminobenzidine tetrahydrochloride (Fluka; Buchs, Switzerland) in 15 ml PBS + 5 µl 30% H₂O₂. The sections were washed three times for 10 min in PBS after incubation Steps b, d, and e. Additional control experiments were performed using 50 µg CA XII protein/microscope slide to block the specific immunoreaction. All the incubations and washings were carried out at RT and the sections were finally mounted in Permount (Fisher Scientific; Fair Lawn, NJ). The stained sections were examined and photographed with a Leitz Aristoplan microscope (Wetzlar, Germany). The intensity of CA XII immunostaining in the renal tumor specimens was scored by two of the investigators (S. Parkkila and T.J. Karttunen) on a scale of 0 to 4 as follows: 0, no reaction; 1, occasional positive cells; 2, weak reaction; 3, moderate reaction; 4, strong reaction. The statistical analyses of intensity scores were performed using one-way analysis of variance.

To determine the cellular distribution of CA XII in the human kidney, the tissue sections were stained using a double immunofluorescence method and analyzed by confocal laser scanning microscopy. The steps in the double immunostaining were as follows: (a) pretreatment of the sections with 1% BSA–PBS for 40 min; (b) incubation for 1 hr with guinea pig anti-human CA II serum diluted 1:50 or goat anti-human AQP2 IgG diluted 5 µg/100 µl, and rabbit anti-human CA XII serum diluted 1:50 in 1% BSA–PBS; (c) washing three times for 5 min in PBS; (d) incubation for 1 hr with 1:50 diluted fluorescein isothiocyanate (FITC)-conjugated goat anti-guinea pig IgG (Sigma Chemical; St Louis, MO) or 1:10 diluted FITC-conjugated donkey anti-goat IgG (Santa Cruz), and 1:30 diluted tetramethylrhodamine isothiocyanate (TRITC)-conjugated swine anti-rabbit IgG (Dakopatts) in 1% BSA–PBS; and (e) washing three times for 5 min in PBS. The immunofluorescent sections were examined with a confocal laser scanning microscope (Leitz CLSM; Leica Microsystems, Heidelberg, Germany).

	Results

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Localization of CA XII in Human Kidney
Fig 1 shows immunoperoxidase staining of CA XII in the human kidney. In the cortex (Fig 1A), the strongest expression of CA XII was located in the epithelial cells of the distal convoluted tubules, thick ascending limb of Henle, and collecting ducts. The immunoreaction was most distinct in the basolateral plasma membrane of the epithelial cells. The epithelium of the proximal convoluted tubules showed only a weak reaction on the basolateral surfaces. In the medulla (Fig 1B), CA XII was located in selected cells in the epithelium of the collecting ducts, where the positive reaction was confined to the basolateral plasma membrane. The control immunostaining of the renal cortex using nonimmune rabbit serum remained negative (Fig 1C).

View larger version (88K): [in this window] [in a new window]   Figure 1. Immunohistochemical staining of CA XII in human renal cortex (A) and medulla (B). Positive immunoreaction for CA XII is seen in the epithelial cells of the distal convoluted tubules (dct), thick ascending limb of Henle (*), and collecting ducts (cd). The most intense reaction is present in the basolateral plasma membrane of the epithelial cells. The epithelium of the proximal convoluted tubules (pct) shows weak staining on the basolateral surfaces. No reaction is seen in the renal cortex stained with nonimmune rabbit serum instead of the anti-CA XII serum (C). Both sera were diluted 1:100. Bars = 40 µm.

Fig 2 provides an additional example of control staining for the specificity of the antibody for CA XII. Antibody-stained sections of renal cortex were compared with sections exposed to antibody in the presence of blocking CA XII protein. The positive staining seen in Fig 2A was blocked by the added antigen (Fig 2B).

View larger version (80K): [in this window] [in a new window]   Figure 2. Immunoperoxidase staining of human kidney using 1:500 diluted anti-CA XII serum in the absence (A) or presence (B) of recombinant CA XII protein. The positive staining was blocked by the added CA XII protein. Bars = 40 µm.

For a more detailed cellular distribution, CA II was used as a marker for the intercalated cells (Sato and Spicer 1982 ; Lonnerholm and Wistrand 1984 ; Brown et al. 1983 ; Brown and Kumpulainen 1985 ) and AQP2 was used to identify the principal cells (Nielsen et al. 1993 ; Knepper and Inoue 1997 ; Loffing et al. 2000 ). Fig 3 shows double immunofluorescence staining of CA XII (TRITC, red color) and CA II (Fig 3A–3D) or AQP2 (Fig 3E and Fig 3F) (FITC, green color) in the human kidney. In the cortex (Fig 3A–3C, Fig 3E, and Fig 3F), CA XII showed positive fluorescent signal in the distal convoluted tubules, thick ascending limb of Henle, and collecting ducts. The weak basolateral signal seen using the immunoperoxidase staining in the proximal convoluted tubules was barely apparent in tissue sections stained using immunofluorescence (compare Fig 1A and Fig 3A). In the medulla (Fig 3D), CA XII showed prominent signal in the epithelial cells of the collecting ducts. The majority of the CA XII-positive cells showed no reaction for CA II. A major exception was observed in the distal tubules, where CA II was expressed in a subset of CA XII-positive cells (Fig 3B). Strong cytoplasmic immunoreaction for CA II was also observed in the collecting ducts of cortex (Fig 3C) and medulla (Fig 3D). The majority of the CA XII-positive cells were identified as principal cells because they did not express CA II. This observation was further confirmed using AQP2 antibodies to identify the principal cells. Fig 3E and Fig 3F show that most AQP2-positive cells in the collecting ducts also expressed CA XII. AQP2 showed the most intense signal in the apical plasma membrane, whereas CA XII was predominantly associated with basolateral membrane.

View larger version (53K): [in this window] [in a new window]   Figure 3. Confocal laser scanning microscopy images of CA XII (TRITC, red color) and CA II (A–D) or AQP2 (E,F) (FITC, green color) in the human renal cortex (A–C,E,F) and medulla (D). CA XII shows positive staining in the distal convoluted tubules (dct), thick ascending limb of Henle (*), and cortical and medullary collecting ducts (cd). CA XII and II do not usually co-localize in the same epithelial cells. A major exception is seen in the distal tubules, in which some epithelial cells express both isozymes (B). In occasional cells of the collecting ducts, the basal membrane appears yellow, indicating co-localization of the isozymes. (E) most AQP2-positive cells in the collecting ducts also stain for CA XII. The strongest signal for AQP2 is located in the apical plasma membrane, whereas CA XII is predominantly associated with the basolateral membrane. AQP2 was demonstrated using C-17 antibody in E and N-20 antibody in F. pct, proximal convoluted tubule. Bars: A–E = 12 µm; F = 10 µm.

Expression of CA XII in Renal Tumors
An outline of the CA XII immunoreactivities estimated in the renal tumors is presented in Fig 4. The mean staining intensity varied from moderate to strong in all tumor categories except angiomyolipoma and Wilms' tumor, the latter showing much weaker immunoreaction compared to other tumors (p<0.001). In clear-cell carcinomas, the immunoreaction showed a trend to correlate with the histological grade, being slightly weaker in well-differentiated carcinomas, although this difference did not reach a statistical significance because of the small number of grade 1 tumors. This finding is illustrated in Fig 5A–5C, in which Fig 5A shows weak signal in grade 1 clear-cell carcinoma, while the positive reaction became stronger in grade 2 and 4 tumors (Fig 5B and Fig 5C, respectively). In all clear-cell carcinomas, the most prominent signal was localized to the plasma membrane of the malignant cells. Fig 5D shows a plasma membrane-associated immunoreaction for CA XII in oncocytoma. Fig 5E demonstrates that the Wilms' tumor specimens were mainly negative for CA XII.

View larger version (28K): [in this window] [in a new window]   Figure 4. Mean intensity of CA XII immunostaining in renal tumors.

View larger version (160K): [in this window] [in a new window]   Figure 5. Immunohistochemical staining of CA XII in renal tumors. (A) Weak plasma membrane-associated staining in grade 1 clear-cell carcinoma. The positive reaction is stronger in grade 2 (B) and 4 (C) tumors. (D) A plasma membrane-associated immunoreaction for CA XII in oncocytoma. (E) Wilms' tumor specimens were mainly negative for CA XII. Antiserum dilution was 1:100. Bars = 40 µm.

	Discussion

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The present observations provide the first opportunity to compare the expression of CA XII to the known distribution pattern of CA activity along the segments of the human nephron and collecting duct. Because CA XII expressed in mammalian cell lines shows distinct CA enzymatic activity (Tureci et al. 1998 ; Karhumaa et al. 2000b ), it may account for some of the basolateral CA activity that has been reported in earlier histochemical studies. Although some species-specific variation exists (Dobyan and Bulger 1982 ), previous studies have demonstrated distinct CA activity in the cytoplasm and in both the apical and basolateral plasma membranes of the proximal convoluted tubule cells and the epithelium of the thick ascending limbs of the loop of Henle (Lonnerholm and Ridderstrale 1980 ; Lonnerholm 1983 ; Lonnerholm and Wistrand 1984 ). In the early part of the distal convoluted tubule, CA activity has been located in the basolateral plasma membrane, whereas the most prominent signal in the collecting ducts has been detected in the cytoplasm of the intercalated cells (Lonnerholm and Ridderstrale 1980 ; Lonnerholm 1983 ; Lonnerholm and Wistrand 1984 ). Comparing the previous histochemical and immunohistochemical studies to the present results on the CA XII expression, one could conclude that the major CA isozymes implicated in renal physiology include at least cytosolic CA II, apical plasma membrane-bound CA IV, and basolateral plasma membrane-associated CA XII. It remains to be studied, however, where the novel membrane-associated isozyme CA XIV (Fujikawa-Adachi et al. 1999 ; Mori et al. 1999 ) is localized and whether its distribution overlaps CA IV or CA XII.

The physiological role of basolateral CA in renal epithelial cells is unclear. In the proximal convoluted tubule, basolateral CA has been suggested to facilitate Na⁺/HCO₃^- co-transport by preventing the development of alkaline disequilibrium pH in the interstitium (Seki et al. 1996 ). In the collecting duct, CA XII expression was predominant in principal cells, which are involved in Na⁺ and water absorption. CA XII might play a role in those processes, because previous studies have indicated its high expression in other tissues with a high water absorption capacity, i.e., colon (Kivela et al. 2000 ) and epididymis (Karhumaa et al. unpublished observations). However, determination of the role of CA XII in ion and water transport in the epithelial cells of renal tubules will require further investigation.

The present immunohistochemical study revealed that CA XII is expressed not only in the normal human kidney but also in most clear-cell carcinomas and oncocytomas. In contrast, the other membrane-associated isozyme, CA IX, shows high expression only in renal carcinomas and is not expressed in normal kidney (McKiernan et al. 1997 ). This difference suggests that these isozymes serve different functions despite their similar subcellular distribution patterns. In fact, the different cellular distribution of CA IX and XII has already been observed in intestine, in which CA IX showed the most prominent signal in the cryptal enterocytes of duodenum and jejunum (Saarnio et al. 1998 ). By contrast, CA XII was absent in the small intestine and showed high expression in the colon enterocytes of the surface epithelial cuff region (Kivela et al. 2000 ). It is notable, however, that these isozymes may be co-expressed in renal and colorectal cancer cells. Interestingly, Ivanov et al. 1998 proposed that they might be functionally involved in the invasion process. This suggestion was based on previous observations that acidification of the extracellular milieu increases the invasive behavior of human melanoma cells (Martinez-Zaguilan et al. 1996 ). Our recent in vitro study implicated CA activity in invasion because acetazolamide, a specific CA inhibitor, reduced the invasion capacity of renal cancer cells by 18–74% depending on the cell line (Parkkila et al. 2000 ). Therefore, the novel tumor-associated isozyme CA XII may have functional significance in the cascade of events involved in the development and spread of cancer.

	Acknowledgments

Supported by grants from the National Institutes of Health (DK40163 and GM34182) to WSS and from the Sigrid Juselius Foundation to SP.

Received for publication May 2, 2000; accepted July 10, 2000.

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