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BASIC SCIENCE |
Department of Physiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, the Netherlands.
Correspondence to Dr. René J.M. Bindels, 160 Cell Physiology, University Medical Center Nijmegen, P.O. Box 9101, NL-6500 HB Nijmegen, the Netherlands. Phone: 31-24-3614211; Fax: 31-24-3616413;
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Abstract |
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Introduction |
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In the kidney, active transcellular reabsorption of Ca2+ takes place in the distal convoluted tubule (DCT) and the connecting tubule (CNT) and constitutes the fine-tuning mechanism determining net urinary Ca2+ excretion (1,9,10). The renal expression and regulation of TRPV5 has been extensively studied. Briefly, TRPV5 is localized along the apical membrane of DCT2 and CNT and is regulated by vitamin D (1,25(OH)2D3), dietary Ca2+, and estrogens, substantiating the role of TRPV5 in renal active Ca2+ transport (11–13). Data on the localization and regulation of TRPV6 have been largely confined to the small intestine, where the expression and regulation by 1,25(OH)2D3 strongly supports the involvement of this channel in the absorption of dietary Ca2+ (14,15). Therefore, TRPV5 is generally suggested to be the epithelial Ca2+ channel primarily responsible for renal transcellular Ca2+ transport, whereas TRPV6 would serve as the apical Ca2+ entry mechanism in the small intestine.
Interestingly, TRPV6 mRNA has been detected in the kidney, but little is known about the localization and regulation of TRPV6 in this organ (16). The elucidation of the precise nephron distribution of TRPV6 is crucial in understanding its physiologic role in the kidney in general and particularly in evaluating the potential contribution of TRPV6 to renal transcellular Ca2+ reabsorption. Importantly, co-localization of TRPV5 and TRPV6 in the kidney may have significant functional relevance, because it was recently shown that TRPV5 and TRPV6 can form heterotetrameric Ca2+ channels with distinct functionality (17).
The aim of the present study was, therefore, to determine the localization and regulation of TRPV6 in the kidney. Immunohistochemistry was performed using a new TRPV6 antibody to elucidate the tubular and subcellular localization of this epithelial Ca2+ channel. In animal experiments, the effect of 1,25(OH)2D3 on renal TRPV6 mRNA and protein expression was studied using real-time quantitative polymerase chain reaction (PCR) analysis and semiquantitative immunohistochemistry.
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Materials and Methods |
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Animal Studies
Experiment 1.
To study the nephron localization of TRPV6 by immunohistochemistry, kidneys were isolated from C57BL6 mice (kindly provided by Dr. J. Loffing, University of Zürich, Switzerland). The tissue fixation procedure consisted of anesthestizing the animals, after which the abdominal aorta was clamped downstream of the renal arteries. Tubing was inserted at the level of the iliac bifurcation into the aorta, pushed up to the aortic clamp, and fixed by a ligature. The vena cava was opened, the aortic clamp was removed, and a fixative solution (50 ml) was allowed to flush the mouse vasculature under high pressure. The fixative consisted of 3% paraformaldehyde (vol/vol) and 0.05% picric acid (vol/vol) dissolved in a 3:2 mixture of 0.1 M cacodylate buffer (pH 7.4) and 10% hydroxyethyl starch (vol/vol) in saline (10). After 5-min fixation, the kidneys were rinsed at hydrostatic pressure by perfusion for 5 min with the cacodylate buffer. Kidneys were subsequently collected and stored at -80°C until further processing.
Experiment 2.
To study the effect of 1,25(OH)2D3 on renal TRPV6 mRNA and protein expression, C57BL6 mice were intraperitoneally injected for 2 days with either 1,25(OH)2D3 at a dose of 100 ng daily (n = 6) or vehicle only (n = 6). Thereafter, animals were sacrificed and kidneys were sampled and either immediately frozen in liquid nitrogen or fixated for immunohistochemistry by immersion in 1% (wt/vol) periodate-lysine-paraformaldehyde (PLP) for 2 h and 15% (wt/vol) sucrose in phosphate-buffered saline overnight. Samples were subsequently stored at -80°C until TRPV6 and TRPV5 mRNA and protein expression levels were determined by real-time quantitative PCR and semiquantitative immunohistochemistry, respectively.
Experiment 3.
To evaluate the mRNA expression of TRPV6 relative to TRPV5 expression in kidney and to determine the quantitative expression in various other tissues, a cDNA panel was constructed. To this end, C57BL6 mice were sacrificed and kidney, bone, prostate, stomach, duodenum, ileum, cecum, colon, pancreas, liver, spleen, brain, lung, heart, and skeletal muscle was sampled. Tissues were subsequently stored at -80°C. The animal ethics board of the University Medical Center Nijmegen approved all experimental procedures.
Immunohistochemistry
The renal localization of TRPV6 was assessed by immunohistochemistry, including co-localization studies using proteins with established distribution patterns as markers for distinct nephron segments. Immunohistochemical staining was performed as described previously (18). In short, either co-immunohistochemical staining or staining of serial sections for TRPV6 with TRPV5, calbindin-D28K, calbindin-D9K, the thiazide-sensitive Na+-Cl- cotransporter (NCC), aquaporin-2 (AQP2), and peanut lectin-binding intercalated cells was performed on 7-µm sections of fixated frozen kidney samples. TRPV5 staining involved immersion of the kidney sections in boiled citrate target retrieval buffer (0.01 M sodium citrate and 0.01 M citric acid, pH 6.0), which was then left to cool for 30 min, and subsequent incubation in 0.3% (vol/vol) H2O2 in buffer (0.15 M NaCl, 0.1 M Tris-HCl, pH 7.5) for 30 min. Sections were incubated for 16 h at 4°C with the primary antibodies: affinity-purified rabbit TRPV6 antibody (1:25), affinity-purified guinea pig TRPV5 antibody (1:1000) (18), guinea pig anti-calbindin-D9K (1:500) (12), mouse anti-calbindin-D28K (Swant, Bellinzona, Switzerland) (1:750), rabbit anti-NCC (1:200) (19), guinea pig anti-AQP2 (1:1000) (20), and FITC-coupled peanut lectin (1:100), respectively. In addition, immunohistochemistry of kidney sections using pre-immune serum and TRPV6 antiserum pre-absorbed for 1 h with the corresponding peptide was performed as negative controls. For detection of TRPV6, calbindin-D9K, calbindin-D28K, NCC, and AQP2 sections were incubated with Alexa-conjugated secondary antibodies. After incubation with biotin-coated goat anti-guinea pig secondary antibody, TRPV5 was visualized using a tyramide signal amplification kit (NEN Life Science Products, Zaventem, Belgium). Images were made using a Nikon Diaphot confocal laser scanning microscope (Tokyo, Japan; MRC-1000; Bio-Rad, Richmond, CA) and a Zeiss fluorescence microscope equipped with a digital photo camera (Nikon DMX1200). For semiquantitative determination of protein levels, images were analyzed with the Image Pro Plus 4.1 image analysis software (Media Cybernetics, Silver Spring, MD), resulting in quantification of the protein levels as the mean of integrated optical density (IOD).
Real-Time Quantitative PCR Analysis
Total RNA was extracted from kidney and other tissues using TriZol Total RNA Isolation Reagent (Life Technologies BRL, Breda, The Netherlands). The obtained RNA was subjected to DNAse treatment to prevent genomic DNA contamination. Thereafter, 2 µg of RNA was reverse transcribed by Moloney-Murine Leukemia Virus-Reverse Transcriptase (M-MLV-RT; Life Technologies BRL) as described previously (18). The obtained cDNA was used to determine TRPV6 and TRPV5 mRNA expression levels as well as mRNA levels of the housekeeping gene hypoxanthine-guanine phosphoribosyl transferase (HPRT) as an endogenous control. PCR primers and fluorescence probes were designed using the computer program Primer Express (Applied Biosystems, Foster City, CA) and purchased from Biolegio (Malden, The Netherlands). The primer sequences for TRPV6 were 5'-ATCCGCCGCTATGCACA-3', 5'-AGTTTTTCTCCTGA ATCTTTTTCCA-3', and 5'-TTCCAGCAACAAGATGGCCTCTACTCTGA-3' for the probe. TRPV5 primer and probe sequences were 5'-CGTTGGTTCTTACGG GTTGAAC-3', 5'-GTTTGGAGAACCACAGAGCCTCTA-3', and 5'-TGTTTCTCAGATA GCTGCTCTTGTACTTCCTCTTTGT-3'. For HPRT, these primers were, respectively, 5'-TTATCAGACTGAAGAGCTACTGTAATGATC-3', 5'-TTACCAGTGGTCAATTATTA CTTCAACAATC-3', and 5'-TGAGAGATCATCTCCACCAATAACTTTTATTGTCCC-3' for the probe. Expression levels were quantified by real-time quantitative PCR on an ABI Prism 7700 Sequence Detection System (PE Biosystems, Rotkreuz, Switzerland).
TRPV6 Promoter Analysis
The general mechanism by which 1,25(OH)2D3 induces gene transcription involves direct interaction of the vitamin D receptor with regulatory domains in the promoter region of the gene known as vitamin D responsive elements (VDRE). To identify putative VDRE, the nucleotide sequence upstream of the ATG codon in the mouse TRPV6 (mTRPV6) gene was analyzed (Genbank accession no. NT039341).
Statistical Analyses
Data are expressed as means ± SEM. Statistical comparisons were tested by one-way ANOVA and Fisher multiple comparison. P values less than 5% were considered statistically significant. All analyses were performed using the Statview Statistical Package software (Power PC version 4.51; Statview, Berkeley, CA) on a Macintosh computer.
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To establish the identity of the additional TRPV6 positive tubules, co-staining of mouse kidney sections for TRPV6 and AQP2, characterizing the CNT and collecting ducts, was performed (9,21). A bright immunopositive TRPV6 signal co-localized with AQP2 in the cortical collecting ducts (CCD) (Figure 4A), outer medullary collecting ducts (OMCD), and inner medullary collecting ducts (IMCD) (Figure 4B). Higher magnification of these AQP2/TRPV6 co-expressing cells showed that, although AQP2 is expressed strictly at the apical membrane, TRPV6 shows additional intracellular staining at the apical side in some of these cells. Taken together, these data indicate that TRPV6 distribution extends from DCT2 into IMCD. In addition, Figures 4C and 4D show that TRPV6 was detected along the apical domain in the intercalated cells of the CD and CNT, respectively (arrows). Co-immunohistochemical staining of TRPV6 with peanut lectin, identifying over 90% of the intercalated cell population, confirmed the strictly apical TRPV6 expression in this cell type (Figure 4F) (22). Therefore, in addition to the principal cells, TRPV6 was clearly expressed in the intercalated cells, which characteristically lack expression of Ca2+ transport proteins.
Identification of Putative VDRE in the TRPV6 Promoter Region
To identify putative VDRE, the mTRPV6 5'UTR was analyzed for the presence of putative hexameric VDRE consensus sequence repeats, known to be involved in the transcriptional regulation of genes by 1,25(OH)2D3. VDRE have been reported to consist of two imperfect repeats separated by a limited number of nucleotide pairs known to contain the hexameric RRKNSA (R = A or G, K = G or T, S = C or G) consensus sequence (23,24). Figure 5 depicts four putative VDRE that were detected within 1500 bp upstream of the mTRPV6 ATG codon (black boxes).
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Discussion |
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By detailed immunohistochemical analysis, the renal segmental and subcellular localization of TRPV6 was elucidated; the results are summarized in Figure 8. In both renal cortex and medulla, TRPV6 expression was predominantly confined to the apical membrane. TRPV6 co-localized with TRPV5 and the calbindins in DCT2 and CNT. It was previously shown that the Na+/Ca2+‘exchanger (NCX1) and the plasma membrane Ca2+-ATPase (PMCA), constituting the basolateral Ca2+ extrusion machinery, are also confined to these nephron segments (9,10). In addition, TRPV6 co-localized with AQP2 in the principal cells of CCD, OMCD, and IMCD. Interestingly, the intercalated cells in CNT and collecting duct also displayed apical TRPV6 expression. Thus, it was concluded that TRPV6 is consistently present along the luminal membranes of DCT2 through IMCD.
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The predominantly apical localization of TRPV6, which has previously been shown to constitute a highly Ca2+-selective ion channel, is in line with a role as apical Ca2+ entry mechanism in kidney (8). The co-localization of TRPV6 with the other key players in active Ca2+ transport in DCT2 and CNT, the main sites of active Ca2+ reabsorption, in conjunction with the positive regulation by 1,25(OH)2D3 in kidney clearly supports our hypothesis that TRPV6 could have functional importance in 1,25(OH)2D3–regulated transcellular Ca2+ reabsorption (10). TRPV6 was originally cloned from duodenum and was recently localized to the brush border membrane of the small intestine, in which calbindin-D9K and PMCA are also known to be expressed (3,14,18). The regulation of TRPV6 expression by dietary Ca2+ and 1,25(OH)2D3 in duodenum and intestinal cell lines has further emphasized the involvement of this channel in dietary Ca2+ absorption (15,30–33). Previously, an essential role was not attributed to TRPV6 in kidney, while TRPV5 was generally considered as the rate-limiting Ca2+ entry step in renal transcellular Ca2+ reabsorption. It is, however, tempting to speculate on the basis of the present renal localization data that TRPV6 could facilitate active Ca2+ (re)- absorption in both kidney and intestine.
We recently demonstrated that the epithelial Ca2+ channels are present in the plasma membrane as functional tetrameric complexes (17). Moreover, TRPV5/TRPV6 heterotetramers were shown to form functional Ca2+ channels in mammalian and Xenopus laevis oocyte expression systems. Depending on their exact subunit composition, these heterotetramers exhibited distinct electrophysiologic characteristics. The co-localization of TRPV6 and TRPV5 along the apical membrane of DCT2 and CNT, which was demonstrated in this study, suggests that these heterotetramers can potentially be formed in the kidney. Hypothetically, co-expression of both epithelial Ca2+ channels may provide these Ca2+ transporting tubules with a pleiotropic set of heterotetrameric channels to cover a broad range of Ca2+ transport kinetics.
Interestingly, TRPV6 expression was also detected in nephron segments not generally implicated in active Ca2+ reabsorption. First, principal cells in cortical and medullary collecting ducts, which are responsible for the fine-tuning of renal Na+ excretion and are highly permeable to water in the presence of vasopressin, displayed distinct apical TRPV6 expression. Second, intercalated cells, known to be involved in urinary acidification, also expressed TRPV6. The absence of supportive Ca2+ transport proteins along the larger part of the CD, as confirmed in this study by the lack of immunopositive staining for calbindins in OMCD and IMCD, precludes involvement of TRPV6 in transcellular Ca2+ reabsorption in these tubules (10). The consistent predominant apical localization would, however, imply that TRPV6 has a functional role as apical Ca2+ entry channel. Hypothetically, TRPV6-mediated Ca2+ influx could affect transport processes in these cells, for instance as part of a hormonal signaling cascade. Vasopressin was shown to induce Ca2+ influx across the apical membrane of renal collecting duct cells, and alterations in intracellular Ca2+ levels are known to affect Na+ reabsorption in these tubules (34–36). In addition, it has been suggested that the action of other hormones, including atrial natriuretic peptide (ANP), parathyroid hormone (PTH), bradykinin, and prostaglandins on transport processes involve Ca2+ signaling (37–39). The tonicity of the pre-urine osmotically challenges tubular epithelial cells constantly, and the resulting cell volume regulation is facilitated by Ca2+ signaling, which has been shown to encompass Ca2+ release from intracellular stores followed by Ca2+ influx from the extracellular compartment (40,41). The identity of the apical Ca2+ entry mechanism in the aforementioned processes has not been elucidated. Therefore, TRPV6 might be a potential candidate.
In this study, TRPV6 and TRPV5 expression levels were quantified in a large set of tissues. Our results showed that TRPV6 mRNA is expressed in nearly all tissues studied but that its expression levels vary greatly. A robust TRPV6 expression was detected in prostate. Although the exact function in this organ remains to be elucidated, previous reports have suggested that TRPV6 expression correlates with prostate carcinoma tumor grade (42,43). In addition, TRPV6 was expressed at lower levels in both kidney and duodenum. The functional relevance of TRPV6 in dietary Ca2+ absorption has been previously illustrated. Therefore, the detection of comparable expression levels in kidney further substantiated that renal TRPV6 expression is indeed quantitatively significant. Of note, substantial TRPV6 expression was detected in bone, an important reservoir of rapidly exchangeable Ca2+, suggesting a role in bone mineralization. Interestingly, TRPV6 mRNA was also abundantly expressed in stomach, which is not known as a site of Ca2+ absorption. This might point to an additional role for TRPV6 in the gastrointestinal tract, distinct from transcellular Ca2+ absorption. Furthermore, TRPV6 was detected at significant levels in brain, lung, and heart, but the functional relevance in these tissues is not clearly envisaged. TRPV5 expression levels were remarkably high in kidney, but TRPV5 was detected in various other tissues as well, including bone and intestine, albeit at considerably lower levels. Given the recent finding that both epithelial Ca2+ channels can combine into heterotetramers with novel functional properties, the variation in relative expression of TRPV6 and TRPV5 in the tissues studied might reflect differential regulation to fine-tune Ca2+ channel kinetics (17). Altogether, these data indicate that, in addition to facilitating active Ca2+ transport in duodenum and kidney, the epithelial Ca2+ channels might also have additional functional roles in the body.
In conclusion, the localization of TRPV6 to the apical domain of cells lining DCT2 to IMCD and the positive regulation by 1,25(OH)2D3 substantiate the functional relevance of TRPV6 in kidney. The co-expression of TRPV6 and TRPV5 implies that a pleiotropic set of heterotetrameric Ca2+ channels could facilitate renal active Ca2+ reabsorption. However, the precise role of TRPV6 in kidney remains to be established, particularly because this epithelial Ca2+ channel was also detected in nephron segments not involved in Ca2+ reabsorption. Given the widespread distribution of TRPV6 throughout the body, additional functions for TRPV6 are indeed conceivable, including a role in Ca2+ signaling.
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Acknowledgments |
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References |
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