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*Department of Cell Physiology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, Nijmegen, The Netherlands; Genetics Unit, Shriners Hospital for Children, Montreal, Quebec, Canada; and Department of Internal Medicine, Erasmus Medical Center, Rotterdam, 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; E-mail: r.bindels{at}ncmls.kun.nl
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Abstract |
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-estradiol (17-E2) is involved in Ca2+ reabsorption via regulation of the expression of ECaC1. The ovariectomized rat model was used to investigate the regulation of ECaC1, at the mRNA and protein levels, by 17-E2 replacement therapy. Using real-time quantitative PCR and immunohistochemical analyses, this study demonstrated that 17-E2 treatment at pharmacologic doses increased renal mRNA levels of ECaC1, calbindin-D28K, NCX1, and PMCA1b and increased the protein abundance of ECaC1. Furthermore, the involvement of 1,25-dihydroxyvitamin D3 in the effects of 17-E2 was examined in 25-hydroxyvitamin D3-1
-hydroxylase-knockout mice. Renal mRNA expression of calbindin-D9K, calbindin-D28K, NCX1, and PMCA1b was not significantly altered after 17-E2 treatment. In contrast, ECaC1 mRNA and protein levels were both significantly upregulated. Moreover, 17-E2 treatment partially restored serum Ca2+ levels, from 1.63 ± 0.06 to 2.03 ± 0.12 mM. In conclusion, this study suggests that 17-E2 is positively involved in renal Ca2+ reabsorption via the upregulation of ECaC1, an effect independent of 1,25-dihydroxyvitamin D3. |
Introduction |
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There is increasing evidence that estrogen plays a physiologic role in the regulation of renal Ca2+ reabsorption. In vivo studies demonstrated that estrogen deficiency was associated with increased renal Ca2+ loss, which could be corrected with estrogen replacement therapy (5,6). Furthermore, there is evidence that estrogen receptors (ER) are also present in the (kidney 7,8). ER localization studies have suggested both proximal and distal tubules as possible sites of action (9,10). However, the underlying mechanism by which estrogen might affect renal Ca2+ handling is still poorly understood. In addition, there is considerable disagreement regarding possible direct effects of estrogen on Ca2+ reabsorption versus indirect effects produced via actions on vitamin D metabolism.
The epithelial Ca2+ channel ECaC1 (or TRPV5), which is observed in renal distal convoluted tubule and connecting tubule cells, is the entry channel involved in transcellular Ca2+ transport (11). Ca2+ entry via ECaC1 is followed by cytosolic diffusion, facilitated by Ca2+-binding proteins (calbindin-D28K and/or calbindin-D9k), and active extrusion of Ca2+ across the basolateral membrane by a high-affinity plasma membrane Ca2+-ATPase (PMCA1b) and a Na+/Ca2+-exchanger (NCX1). In this active process, ECaC1 probably forms the final regulatory target for hormonal control (12,13). Therefore, ECaC1 could be a target for estrogen in the regulation of Ca2+ reabsorption.
The aim of this study was to determine whether estrogen acts on the distal part of the renal tubule by increasing the expression of ECaC1, which could result in increased Ca2+ reabsorption. We used the ovariectomized (OVX) rat model of estrogen deficiency to investigate changes in ECaC1, at the mRNA and protein levels, with estrogen replacement therapy. The involvement of the important calciotropic hormone 1,25(OH)2D3 in estrogen effects was examined in 25-hydroxyvitamin D3-1-hydroxylase (1-OHase)-knockout mice, as a vitamin D-deficient model (14). This study indicates that estrogen upregulates ECaC1 expression in the kidney, thereby regulating Ca2+ reabsorption, and that estrogen exerts this effect independently of 1,25(OH)2D3.
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Materials and Methods |
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-estradiol (17-E2) (Sigma Chemical Co., St. Louis, MO) or vehicle (gelatin and mannitol), added to the pelleted food, each day. Sham-operated animals served as control animals. OVX animals were given either the vehicle alone, 2 x 32 µg 17-E2/d, 2 x 125 µg 17-E2/d, or 2 x 500 µg 17-E2/d. Treatment was started immediately after OVX and lasted for 7 d. Before the end of treatment, overnight urine samples were collected. On the last day, the rats were euthanized. Blood was collected from the abdominal aorta, the uterus was excised and weighed, and the kidneys were dissected and immediately frozen in liquid nitrogen.
Experiment 2.
Homozygous, 9-wk-old, male, 1-OHase-knockout mice (14) were housed individually in a light- and temperature-controlled room. Both deionized water and standard pelleted food were available ad libitum throughout the experiment. The mice were randomized into the following two groups (with each group consisting of four mice): homozygous mice and homozygous mice given infusions of 17-E2. Osmotic minipumps (model 1007D; Alzet, DURECT Corp., Cupertino, CA) were used for rate-controlled delivery of 17-E2; these pumps release their contents at a rate of 0.5 µl/h for 7 d. The pumps were filled with the desired solution and implanted subcutaneously in the backs of the mice. The infusion dose for the 17-E2-treated mice was 10 µg/d, and control mice received vehicle solution alone (15% ethanol/50% DMSO/35% water, vol/vol). After 7 d, mice were euthanized, blood was collected via orbital puncture, and kidneys were dissected and immediately frozen in liquid nitrogen. The animal ethics boards of the University of Nijmegen and Shriners Hospital for Children (Montreal, Quebec, Canada) approved all animal experimental procedures.
Analytical Procedures
Serum Ca2+ concentrations were analyzed by using a colorimetric assay kit, as described previously (15). Serum 17-E2 levels were measured by using an extraction procedure with diethyl ether, followed by RIA (DPC, Los Angeles, CA) (16).
RNA Isolation, Reverse Transcription, and Quantitative PCR
Total RNA from kidney cortex was isolated by using TriZol reagent (Life Technologies, Breda, The Netherlands), according to the protocol described by the manufacturer. RNA was treated with DNase, to prevent genomic DNA contamination, and was finally resuspended in diethylpyrocarbonate-treated water filtered with a MilliQ system (Millipore, Bedford, MA). Total RNA (2 µg) was subjected to reverse transcription using Moloney murine leukemia virus reverse transcriptase (Life Technologies), as described previously (17). Expression levels of renal ECaC1, calbindin-D28K, calbindin-D9K, NCX1, and PMCA1b mRNA were quantified by real-time quantitative PCR, using an ABI Prism 7700 sequence detection system (PE Biosystems, Rotkreuz, Switzerland). The expression level of hypoxanthine-guanine phosphoribosyl transferase was used as an internal control, to normalize differences in RNA extractions, the degree of RNA degradation, and reverse transcription efficiencies. Primers and probes targeting the genes of interest were designed by using Primer Express software (Applied Biosystems, Foster City, CA) and are listed in Table 1. The 3'-ends of the probes were labeled with the quencher dye 6-carboxytetramethylrhodamine. The 5'-ends of all probes were labeled with the reporter dye 6-carboxyfluorescein (Biolegio, Malden, The Netherlands).
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Statistical Analyses
Values are expressed as mean ± SEM. Differences between groups were tested by using one-way ANOVA and were further evaluated by using Fisher’s multiple-comparison procedure (18). Differences in means with P < 0.05 were considered statistically significant. All analyses were performed by using the Statview statistical package (Power PC version 4.51; Statview, Berkeley, CA) on a Macintosh computer.
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Results |
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-E2 Treatment on Rats-E2 treatment induced significant reductions in weight, with the greatest decrease being observed for the OVX/high-dose 17-E2-treated rats (Table 2). OVX resulted in the expected atrophy of the uterus, which was prevented by 17-E2 therapy in OVX/high-dose 17-E2-treated rats (Table 2). Serum 17-E2 levels were reduced in untreated OVX rats, confirming OVX, whereas supplementation with the highest 17-E2 dose resulted in significantly higher serum 17-E2 levels (Table 2). 17-E2 treatment reduced serum Ca2+ levels, resulting in slightly but significantly lower serum Ca2+ levels in the OVX/high-dose 17-E2-treated group.
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-E2 on ECaC1 Expression in Rat Kidneys-E2 on ECaC1 mRNA expression, real-time quantitative PCR was performed with total RNA isolated from kidney cortex (Figure 1A). The data demonstrated that 17-E2 supplementation, using the highest dosage, for estrogen-depleted rats resulted in a 2.5-fold increase in ECaC1 mRNA expression, compared with OVX rats. The expression levels of other Ca2+-transport proteins involved in transcellular Ca2+ transport, namely calbindin-D28K, NCX1, and PMCA1b, were also determined. More than twofold upregulation of calbindin-D28K mRNA expression was observed in OVX/high-dose 17-E2-treated rats, compared with OVX rats (Figure 1B). In addition, significant increases in the expression of both NCX1 (5.5-fold) and PMCA1b (1.5-fold) mRNA in OVX/medium-dose 17-E2-treated rats, compared with OVX rats, were demonstrated (Figure 1, C and D). Next, the abundance of ECaC1 protein in kidneys was examined. Figure 2A presents representative immunofluorescence labeling of distal tubules in sections of kidney cortex from OVX and OVX/high-dose 17-E2-treated rats. More ECaC1 protein was detected in tissue from the supplemented rats, as indicated by the increased staining in the kidney cortex. In these immunopositive tubules, ECaC1 was localized to the apical membrane of distal tubular segments. For semiquantitative assessment of ECaC1 protein expression, the relative amounts of immunopositive tubules in 10 to 15 randomly selected microscopic fields were counted for each kidney cortex section. Figure 2B presents the average values for each experimental group. The levels of ECaC1 expression in OVX/medium-dose 17-E2-treated and OVX/high-dose 17-E2-treated rats were significantly higher than those in OVX rats.
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-E2-Induced Increases in Plasma Ca2+ Levels in 1,25(OH)2D3-Deficient Mice-OHase-knockout mice is growth retardation, as illustrated by their low body weights (Table 3), compared with wild-type animals (>20 g) (14,19). After 17-E2 treatment, no significant change in body weight was observed. The 1-OHase-knockout mice exhibited severe hypocalcemia, with plasma Ca2+ levels of 1.63 ± 0.06 mM. Surprisingly, after treatment with 17-E2, plasma Ca2+ levels significantly increased to 2.03 ± 0.12 mM. Measurement of serum 17-E2 levels confirmed the increase in 17-E2 levels after treatment (Table 3).
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-E2 on ECaC1 Expression-E2 supplementation on the expression of ECaC1 and other renal Ca2+-transport proteins, control and 17-E2-treated 1-OHase-knockout mice were used. A 2.5-fold increase in ECaC1 transcript levels in the kidney cortex of 17-E2-treated mice, compared with control mice, was observed (Figure 3A). However, in contrast to the upregulation of ECaC1, no significant changes in the expression of calbindin-D28K, NCX1, or PMCA1b were observed after treatment (Figure 3, B to E). Immunohistochemical analyses confirmed the increase in ECaC1 expression, after 17-E2 treatment, at the protein level, as indicated by the increased staining in the kidney cortex of 17-E2-treated mice, compared with control mice (Figure 4A). Semiquantitative assessment of the relative amounts of immunopositive tubules demonstrated a significant increase in the expression of ECaC1 protein after 17-E2 treatment (Figure 4B).
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Discussion |
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Estrogen replacement therapy for the OVX rats, at pharmacologic doses, resulted in significant upregulation of ECaC1 mRNA and protein expression. ECaC1 protein was observed exclusively at the apical side of distal tubular cells, in agreement with previous studies (17,20). The increased mRNA levels after 17-E2 treatment could be attributable to enhanced transcriptional activity or mRNA stabilization. In addition to increases in mRNA abundance, translational regulation of ECaC1 might occur, ultimately resulting in increased channel activity at the apical cell surface. In general, estrogen activates the ER, which subsequently regulates gene transcription by binding to the classic estrogen response elements. ER have been observed in the kidney, especially in the proximal tubules, where 17-E2 is retained in the nuclei (10). However, Davidoff et al. (9) determined, using autoradiography, that ER are also localized (albeit to a lesser extent) in the distal tubules, the site of ECaC1 expression. Interestingly, Weber et al. (21) recently described an estrogen response element in the promoter sequence of the mouse ECaC2 gene; the response element was not present in the mouse ECaC1 gene. Alternatively, transcriptional activation by the estrogen-liganded ER can be mediated via activator protein 1 (AP-1) binding sites or GC-rich stimulatory protein (Sp1) binding sites (22,23). Importantly, the human ECaC1 promoter contains several of these AP-1 and Sp1 sites (20,24). Several of these AP-1 and Sp1 binding sites can be observed in the 5'-upstream region of the translation initiation site in the mouse ECaC1 gene and could be involved in the positive effect of 17-E2 treatment on ECaC1 mRNA expression. Future studies using ER-knockout mice should indicate whether the observed effects on ECaC1 expression are mediated via ER or an unknown mechanism. Furthermore, detailed promoter analysis is necessary to identify the regulatory sites involved in this estrogen-mediated regulation of ECaC1.
Because the activity of ECaC1 is tightly controlled by cytosolic Ca2+ concentrations, a sufficient cytosolic Ca2+-buffering capacity is essential (25,26). This study demonstrates that, in rat kidney, ECaC1 and calbindin-D28K are synchronically upregulated, suggesting that this requirement is fulfilled. There is evidence that an estrogen-responsive promoter exists in the 5'-upstream region of the mouse calbindin-D28K gene (27). Criddle et al. (28) demonstrated that estrogen treatment increased renal calbindin-D28K mRNA levels in OVX rats, several hours after administration. In addition, tremendous upregulation of NCX1 and a slight but significant increase in the levels of PMCA1b (both of which are members of the basolateral extrusion system) were observed. In agreement with this finding, it has been suggested that Ca2+ extrusion across the basolateral membrane is mediated primarily by NCX1 (13,29). Taken together, these findings suggest a positive effect of 17-E2 on renal tubular reabsorption of Ca2+. However, 17-E2 treatment resulted in decreased serum Ca2+ levels. This effect of estrogen therapy on serum Ca2+ levels was previously observed among human subjects (30). This apparent discrepancy can be explained on the basis of the increased Ca2+ requirements for estrogen-deficient animals. Correction of estrogen deficiencies results in decreased bone resorption and increased formation, causing slight decreases in plasma Ca2+ concentrations (3).
The relationship between estrogen actions in the kidney and vitamin D metabolism is still unclear. 1,25(OH)2D3 is a major regulator of Ca2+ homeostasis, and the kidney is the principal site of its synthesis (31). In the literature, conflicting data have been presented regarding direct versus indirect effects of 17-E2 on Ca2+ reabsorption. Some studies demonstrated that estrogen treatment increased 1,25(OH)2D3 levels among postmenopausal women (32). One study demonstrated that 17-E2 was retained in the cell nuclei of proximal tubules, where the synthesis of 1,25(OH)2D3 takes place (10). With the use of cultured opossum kidney cells, a suppressive effect of 17-E2 on 1-OHase activity was demonstrated (33). Among postmenopausal women, however, estrogen replacement therapy resulted in unchanged or increased renal 1-OHase activity (30,34). In previous studies, it was demonstrated that Ca2+ reabsorption was stimulated by 1,25(OH)2D3 (35,36). Furthermore, 1,25(OH)2D3 enhances the renal expression of ECaC1 and Ca2+-transport proteins (calbindin-D28k, NCX1, and PMCA1b), as demonstrated in previous studies (20,29,36,37). In contrast, some studies suggested a direct effect of 17-E2 on Ca2+ reabsorption, independent of vitamin D (3,28).
1-OHase-knockout mice represent an ideal animal model for studies of the effects of 17-E2 on transcellular Ca2+ transport independent of 1,25(OH)2D3. As demonstrated in this study and reported by the two laboratories that engineered the 1-OHase-knockout mice, these animals exhibit severe hypocalcemia (14,19). Treatment with 17-E2, at pharmacologic doses, results in significant increases in serum Ca2+ levels (to subnormal concentrations) and increases in the expression of ECaC1. These findings suggest a positive effect of 17-E2 on plasma Ca2+ levels, which might be attributable to increased renal Ca2+ reabsorption through ECaC1, independently of 1,25(OH)2D3. Therefore, 17-E2 could be directly involved in Ca2+ reabsorption via upregulation of ECaC1 gene expression in the absence of circulating 1,25(OH)2D3. In contrast, the expression of the other transport proteins remained unchanged, indicating 1,25(OH)2D3 dependence for the regulation of calbindins, NCX1, and PMCA1b. An explanation for this discrepancy could be that, in addition to 17-E2, 1,25(OH)2D3 is required for optimal stimulation of Ca2+ transport, eventually leading to normalized Ca2+ levels. Another explanation could be that, in addition to upregulated expression of ECaC1, sufficient calbindins and extrusion proteins are present to facilitate active transport, leading to normalization of serum Ca2+ levels. This is in accord with previous studies that suggested that ECaC1 represents the rate-limiting step in active Ca2+ transport (12,13). Also, the intestine must be considered to contribute to the increase in serum Ca2+ levels. It was previously demonstrated that estrogen has a positive effect on intestinal Ca2+ absorption, and it has been suggested that this effect is independent of 1,25(OH)2D3 (16,38,39). ECaC1 and its homolog ECaC2 are present in the duodenum, as are other transport proteins necessary for active Ca2+ transport (11,17).
In addition to direct effects on bone, estrogen deficiencies might directly affect renal and intestinal Ca2+ handling, resulting in a continuing negative Ca2+ balance. Furthermore, interactions with other calciotropic hormones in these tissues must be considered. Because of the high prevalence of osteoporosis, intensive investigations have been performed to clarify the underlying pathophysiologic mechanisms. This study provides evidence that 17-E2 is positively involved in renal Ca2+ reabsorption via the upregulation of ECaC1, an effect independent of 1,25(OH)2D3. Future detailed studies of the cellular mechanisms of estrogen actions in bone, kidney, and intestine should lead to novel insights regarding the treatment of estrogen-associated disorders.
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