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ARTICLE |
Regulates Gene Expression in the Kidney
Genomics Department (S.A.J., E.L.B., K.F., C.T.), Wyeth Research, Cambridge, Massachusetts 02140; and Women’s Health Research Institute (H.A.H., X.Z., K.L., M.V.L., D.K.S., M.J.E.), Wyeth Research, Collegeville, Pennsylvania 19426
Address all correspondence and requests for reprints to: Dr. Mark Evans, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: evansm{at}wyeth.com.
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Abstract |
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-selective agonist propylpyrazole triol acted similarly to E2, together suggesting an ER-mediated mechanism. Several genes were induced within 2 h of E2 treatment, suggesting a direct activity of ER within the kidney. Finally, the combination of the activation function (AF)1-selective agonist tamoxifen plus ERKOCH mice expressing an AF1-deleted version of ER allowed delineation of genes with differing requirements for AF1 or AF2 activity in the kidney. |
Introduction |
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expression predominant in uterus, pituitary, kidney, and adrenal gland and ERß expression predominant in ovarian granulosa cells, prostate, bladder, and lung (7). Similarly, recent studies of transgenic mice containing synthetic estrogen response element (ERE) reporter constructs have suggested that acute treatment with estrogens can regulate gene expression in numerous organs (8, 9). Estrogen replacement therapy is used by a large percentage of postmenopausal women (10) and is usually administered for several years. For osteoporosis, replacement therapy is recommended to be administered for at least 5 yr, and preferably for 10 yr, to achieve maximal protective effects (reviewed in Ref. 11). Little is currently known about the effects of chronic estrogen treatment on gene expression throughout the body. To address this issue, we have initiated a large-scale analysis of gene expression in the mouse, after chronic (6 wk) estrogen treatment.
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Materials and Methods |
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KOCH mice (12), ERßKO mice (13), or ERCHERßKO mice (13) were placed on a casein-based diet at approximately 6 wk of age. One week later, the animals were ovariectomized. Commencing the day after ovariectomy, each animal received a daily sc treatment with vehicle (50% dimethylsulfoxide, 50% PBS) or vehicle-containing treatments for 6 wk. Each group consisted of six or seven animals. Approximately 2 h after the final treatment (
3 h after commencement of the light cycle), the animals were euthanized, and selected tissues were frozen in liquid nitrogen for RNA analysis or on dry ice for histology. All animals were treated in accord with accepted standards of care as specified by the Wyeth animal care committee.
GeneChip microarrays
Total RNA was prepared separately from each individual organ by using Trizol (Invitrogen, Carlsbad, CA) followed by subsequent repurification on RNeasy columns (QIAGEN, Valencia, CA). In general, two pools of RNA were created using equal amounts of RNA from three mice. For small organs, such as pituitary, the repurification step was eliminated, and an equal amount of RNA from six animals was combined.
Target preparation and array hybridization
Total RNA was used to generate biotin-labeled cRNA target as described (14), which was hybridized to the murine MG_U74Av2 probe arrays (Affymetrix, Santa Clara, CA) for 16 h at 45 C. Eleven biotin-labeled cRNAs at defined concentration were spiked into each hybridization and were used to convert average difference values to frequencies expressed as parts per million (15).
Data analysis
Pairwise comparisons were made between treatments. We calculated the fold change ratio, the P value based on Student’s t test, the number of present calls, and the expression level for each comparison. A confidence score (CS) was defined as CS(x) = FC(x) + PV(x) + PC(x) + EL(x), where FC, PV, PC, and EL are scores assigned to the fold change, P-value, number of present calls, and the expression level, respectively. FC(x) was assigned 5 if the fold change ratio was greater than 1.95 and was assigned 0 if the ratio was between 1.95 and 1.5. PV(x) was assigned 3 if the P-value was less then 0.05 and was assigned 2 if the P-value was between 0.05 and 0.1. PC(x) was assigned 3 if at least 50% of the samples are called P by the Affymetrix algorithm and assigned 1 if only 25% of the samples are called P. EL(x) was assigned 3 if at least two samples had a frequency value of 20 or greater and assigned 1 if two samples only had a frequency greater then 15. Penalty points were assigned if the fold change was less then 1.5, the P-value was greater than 0.2, or the frequency values were less than 15 ppm. CS(x) ranged from -14 to 14, with qualifiers having a score of 14 considered the most significant changes. Genes with 11 or more points in any one pairwise comparison were considered to be significant and were included for further analysis.
Real-time PCR
RNA samples were prepared from each individual organ using Trizol (Invitrogen). The RNA was subsequently treated with deoxyribonuclease to remove residual genomic DNA and repurified by QIAGEN RNeasy kit. The RNA concentration was adjusted to 0.1 mg/ml for assay. RNA expression levels were determined by real-time RT-PCR with an ABI PRISM 7700 Sequence Detection System according to the manufacturer’s protocol. The sequences of primers and labeled probes used for mRNA detection are shown in Table 1
. In the kidney, expression levels for each gene were normalized for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Because GAPDH expression in the uterus is induced by estrogens, uterine results were normalized for total RNA content using the RiboGreen method (Molecular Probes, Inc., Eugene, OR). Data are presented as the mean ± SE of the mean. Statistical difference from vehicle treated animals was determined by ANOVA of log transformed data with Huber weighting, with P = 0.01 chosen as the cutoff for statistical significance.
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Results |
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or ERß. For ER regulation, the basal expression level was predicted to be the same in WT and ERßKO mice, with E2 induction or suppression occurring in both WT and ERßKO mice (Fig. 1). For ERß regulation, basal expression was predicted to be the same in WT and ERßKO mice, with E2 induction or suppression occurring in WT mice but not in ERßKO mice. ER pattern regulations were found in well-known estrogen target tissues, such as the uterus (514 inductions, 19 repressions), pituitary (56 inductions, 30 repressions), and bone marrow (3 inductions, 3 repressions). In contrast, essentially no genes could be discerned that fit the predicted ERß regulation pattern in any tissue.
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). Similar results were obtained in the rat, where E2 treatment also induced expression of many genes, such as GADD45G, which had not been detected in the mouse study (data not shown). To further characterize E2 regulation of gene expression in the kidney, in situ hybridization was used to localize E2 induction of cytochrome P450, subfamily VIIB (oxysterol 7-hydroxylase), polypeptide 1 (CYP7B1), tissue factor (TF), signal transducer and activator of transcription 5A (STAT5A), and GADD45G. In each case, induction of gene expression occurred in the juxtamedullary region of the kidney (Fig. 3). Estrogen regulation of STAT5A and GADD45G also occurred in the rat kidney juxtamedullary region (Fig. 4), demonstrating that the estrogen responsiveness of kidney is not limited to the mouse.
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). Although this is approximately 10-fold greater than the ED50 dose of E2 required for uterine weight increases, the ED50 for gene induction in the uterus can vary by 20-fold, from 0.2 µg/kg·d E2 for BCAT1 induction to 2.7 µg/kg·d for c-fos (Fig. 5), similar to that reported previously for c-fos in the rat uterus (17). Thus, E2 induction of gene expression in the kidney did not require higher E2 doses than those required for some well-characterized uterine responses, such as induction of c-fos.
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), with maximal inductions occurring at 2–4 h after E2 treatment. By 24 h after the single E2 treatment, the expression levels of these genes had all returned to basal levels. In contrast, a single E2 treatment had no effect on the expression of CYP7B1. Mice treated with E2 daily for 6 wk had similar levels of TF, STAT5A, GADD45G, and BCAT1 before the final E2 treatment (24 h since the previous E2 treatment), consistent with the return to baseline expression for these four genes 24 h after a single E2 treatment. Further, the kinetics of gene induction for CYP7B1, TF, GADD45G, and STAT5A were very similar in mice treated with either vehicle or E2 for the preceding 6 wk. The level of CYP7B1 was elevated in the mice receiving 6-wk E2 treatment and was neither significantly elevated 2 h after the final E2 treatment nor reduced 48 h after the last E2 treatment. The kinetics of regulation of TF, STAT5A, GADD45G, and BCAT1 thus were consistent with direct ER activity within the kidney, whereas CYP7B1 induction seemed to be secondary to other physiological changes after chronic E2 treatment.
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in the induction of kidney gene expression was obtained by treatment with 4-propyl-1,3,5-Tris(4-hydroxy-phenyl) pyrazole [propylpyrazole triol (PPT)], a compound which exclusively activates ER but not ERß (18). PPT induced expression of CYP7B1, TF, STAT5A, and BCAT1 to a similar extent as did treatment with E2 (Fig. 7). Further, two ERß-selective agonists (W-0292 and W-0070, both approximately 75-fold selective for ERß compared with ER by in vitro binding assays; data not shown) failed to stimulate expression of any of these four genes (Fig. 7).
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KO mice (12), now designated as ERKOCH mice (19), in fact express an ER protein lacking only activation function (AF)1, due to alternative splicings of the exon containing the targeted knockout mutation (20, 21). The resulting truncated ER proteins, referred to here as 
AF1-ER, have the ability to stimulate expression of a synthetic ERE-driven promoter (21). As found previously for ERKOCH mice, the level of this misspliced transcript in the uterus of ERCHERßKO mice was lower than the level of full-length message in WT mice (Fig. 8). Again as expected, the amount of intact ER mRNA was much lower in the whole kidney than in uterus from WT mice. However, the level of AF1-ER mRNA was actually greater in the ERCHERßKO kidney than was intact ER mRNA in WT kidney. No ERß mRNA could be detected in either uterus or kidney from the ERCHERßKO mice.
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AF1-ER at significant levels in the kidney allows determination of the relative contribution of AF1 and AF2 to E2 regulation of individual genes. To determine whether AF1 or AF2 regions of ER were required for induction of gene expression in the kidney, WT, ERCHERßKO, or ERKOCH mice were treated with E2 or the selective ER modulator (SERM) tamoxifen, which induces an antagonist conformation of helix 12 in the ER AF-2 (22) but stimulates gene expression through an ER AF-1-dependent mechanism (23). TF expression in the kidney was induced by both E2 and tamoxifen in WT mice (Fig. 9A). Neither compound induced TF expression in ERCHERßKO or ERKOCH mice. In contrast, BCAT1 was also induced by both E2 and tamoxifen in WT mice. However, in ERCHERßKO or ERKOCH mice, E2 stimulated BCAT1 expression but tamoxifen did not. Activity in the double-knockout animals excludes ERß as a possible mechanism, whereas the ability of ICI-182780 to block the E2 induction in the ERKOCH indicates an ER-dependent mechanism.
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). In the uterus, the pattern of TF regulation by E2 and tamoxifen in WT, ERCHERßKO, and ERKOCH mice was the same as in the kidney. In contrast, BCAT1 expression in the uterus was induced by E2 and tamoxifen treatment of WT mice but not by either treatment in ERCHERßKO or ERKOCH mice. This pattern is distinct from that seen for BCAT1 in the kidney and resembles that seen for TF. The lack of induction in ERCHERßKO or ERKOCH was not attributable to a complete lack of E2 activity in the uteri from these mice, because c-fos (Fig. 9) and several other genes (not shown) were still partially induced in the uteri of these mice.
A potential model for these results is presented in Fig. 9B. In WT animals, expression of TF in the kidney is induced by ER predominantly through an AF1-dependent mechanism. In mice that express only AF1-ER, E2 and tamoxifen are unable to induce expression of TF. Induction of BCAT1 may use either AF1- or AF2-dependent mechanisms. Thus, E2 is still able to induce BCAT1 expression in mice expressing AF1-ER. Tamoxifen is unable to stimulate BCAT1 expression in the kidney of these mice because tamoxifen functions as an agonist only through AF1. The coactivator responsible for the AF1-dependent activation of TF and BCAT1 in the kidney and uterus could be a ubiquitously-expressed coactivator, whereas the coactivator responsible for AF2-dependent activation of BCAT1 might have expression limited to the kidney but not the uterus.
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Discussion |
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or -ß are found in almost all organs of the body, yet relatively few tissues are considered targets for estrogen action. To begin to develop a more complete understanding of estrogen biology, we here begin the characterization of estrogen-responsive genes in 13 tissues from WT and ERßKO mice. In general, many tissues showed patterns of E2 regulation consistent with an ER mechanism, including such known target organs as uterus, pituitary, and bone. Surprisingly, no E2 regulations were found that fit the expected pattern for ERß regulations. This was true even in organs expressing moderately high levels of ERß, such as the bladder and lung (7). At least three mechanisms could explain our lack of detection of expected ERß responses. First, it has been proposed that a major function of ERß is to modulate the activity of ER (24). For example, expression of the Ki-67 protein was constitutively elevated in the uterus of ERßKO mice; i.e. in the ERßKO mice, its expression was always equivalent to the E2-stimulated levels in WT animals (25). The survey criteria used here would not detect this pattern. Further analysis of these data has revealed many genes in multiple tissues that also have this nonclassical pattern of regulation, whereby expression is constitutively elevated in both vehicle- and E2-treated ERßKO mice (data not shown). Second, our analysis of whole organs may easily miss regulations occurring in only selected cell subtypes within an organ. For example, our initial analysis of kidney did not originally identify GADD45G as being regulated by E2, because GADD45G expression is regulated only in tubule epithelial cells. The unregulated expression of GADD45G throughout most of the kidney sufficiently diminished the fold induction, so as to be less than 2-fold in whole-organ samples. The combination of laser capture microdissection with microarray technology (26) may allow detection of ERß-regulated genes with a classical pattern of regulation. Finally, we have recently demonstrated that ER inhibition of inflammatory process in the mouse liver does not require ER induction of gene expression, but rather seems to operate through nonclassical mechanisms such as coactivator competition between ER and NF
B (27, 28). ERß might thus represent a very selective method for inhibiting inflammatory processes without inducing gene expression. Further studies will be required to delineate between these multiple possibilities.
This global survey demonstrates that the kidney had a very large number of regulated genes. It is likely that the number of genes reported here is actually an underestimate, because less abundant mRNAs present only in the cells showing E2 regulation may have been diluted using RNA from the entire kidney. Both genetic approaches (Fig. 2) and pharmacological approaches (Fig. 6) demonstrated that E2 regulation in the kidney was mediated through ER. Expression of CYP7B1, TF, STAT5A, and GADD45G were regulated only in the juxtamedullary region of the cortex (Fig. 3). The histology pattern of expression of these genes is very similar to that shown for several proximal tubule-specific genes (29). Several of the E2-regulated genes have expression limited to the proximal tubules. For example, kidney injury molecule-1, the rat counterpart of mouse E2-induced T-cell Ig and mucin domain (TIM)1 and TIM2 (30), is expressed in proximal tubule epithelial cells (31). The E2-regulated gene CYP27B1 (1-hydroxylase) is also known to be expressed only in proximal tubules (32, 33). Finally, 3H-E2 binding localizes to proximal tubule cells in rats (34). Because the kinetics of E2 induction for most (TF, STAT5A, GADD45G, and BCAT1), but not all (CYP7B1), genes in the kidney were similar to those for induction of primary response genes in the uterus (17), these combined results suggest that ER directly regulated gene expression in tubule epithelial cells.
Although the observed regulations in the kidney were mediated by ER, the mechanism of activation of gene expression by ER was gene specific. Thus, studies using tamoxifen, which activates ER through AF1, along with studies using ERKOCH mice (which express AF1-ERKO), together suggest that E2 induction of TF expression occurred predominantly through an AF1-dependent mechanism, whereas E2 induction of BCAT1 expression occurred through both AF1 and AF2 mechanisms (Fig. 9). The ED50 values for E2 stimulation of these genes were very similar (Fig. 5). Thus, whether a gene is induced through either an AF1 or AF2 mechanism does not influence the sensitivity of the gene, in the kidney, to plasma estrogen levels. Rather, the binding of E2 to ER seems to be the rate-limiting step in induction of gene expression in the kidney. The maximal fold regulation clearly depended on the gene and may still be dependent on whether an AF1- or AF2-dependent pathway is used.
The dependence on either AF1 or AF2 for a particular gene varied between tissues. For example, E2 induction of BCAT1 in the kidney seemed to use either AF1 or AF2 mechanisms, yet E2 induction of BCAT1 in the uterus seemed to use only an AF1-dependent mechanism (because E2 induction of BCAT was completely lost in the ERKOCH uterus but not in the kidney). E2 induction of c-fos and other genes in the ERKOCH uterus suggests that the AF2-dependent activation pathway was not completely eliminated in the uterus of the ERKOCH animals. A potential explanation for these results is a difference in coactivator expression between the uterus and kidney, coupled with the use of different coactivators for different genes. Coactivator levels can vary between tissues (27, 35), and the high levels of SRC-1 in Ishhikawa endometrial cells, compared with MCF-7 mammary carcinoma cells, mediate the cell-specific actions of tamoxifen (36). The high expression levels of the ER coactivator ERAP140 in the kidney cortex (37) might allow AF2-dependent activation of BCAT1 in the kidney but not in the uterus. Studies in coactivator knockout animals should allow further analysis to determine which particular coactivators are important for ER regulation of gene expression in different tissues.
Analysis of 10 kb of upstream putative promoter sequences of E2-induced genes identified good matches to the consensus ERE (38) in only a few genes, although ERE half-sites could be identified in most promoters (not shown). Many of these genes may be activated through nonclassical ER mechanisms, such as the combination of an ERE half-site with Sp1-binding sites (39) or AP-1 sites (40). Additionally, E2 induced expression of the transcription factors E74-like factor 3 (ELF3), STAT5A, and STAT5B. It is possible that E2 induction of these transcription factors resulted in the subsequent increase in expression of the remaining genes. For example, cytokine-inducible Src homology 2-containing protein 2 (CIS2) is a known target for induction by STAT transcription factors (41), suggesting that the E2 induction of CIS2 may have been mediated indirectly through the E2 induction of STAT5A and STAT5B. The mouse STAT5A promoter does contain a good match to the consensus ERE. Additionally, a major element controlling CYP27B1 promoter activity is a binding site for members of the Ets transcription factor family (42). E2 induction of ELF3, a member of the Ets family, might thus have been responsible for the induction of CYP27B1.
The identity of genes regulated by estrogens in the kidney may provide insights into the molecular mechanisms that underlie some of the known physiological effects of elevated estrogens occurring before ovulation or during pregnancy. Interestingly, the ED50 value for E2 activation of gene expression in the kidney was about 10-fold higher than that required for uterine weight increases (Fig. 5) and comparable to the highest ED50 values for genes in the uterus. This was true even for genes such as BCAT1, which was stimulated by E2, with an ED50 of only 0.2 µg/kg·d in the uterus but 3.4 µg/kg·d in the kidney. This mechanism may function to ensure that these genes are normally regulated in the kidney only when very high levels of estrogens are present, as during pregnancy.
One E2-regulated gene in the kidney with potential biological significance is CYP27B1, the enzyme responsible for the rate-limiting conversion of inactive 25-hydroxy vitamin D3 into active 1,25-dihidroxyvitamin D (43). This hydroxylation occurs in the proximal tubules of the kidney and has been shown to be stimulated by estrogen treatment of birds (44). Urinary calcium excretion is increased in postmenopausal women, whereas estrogen treatment reduces urine calcium levels (45, 46). Activation of renal epithelial vitamin D receptors increases the levels of calcium-binding proteins and increases the rate of calcium transport (47). Thus, E2 induction of CYP27B1 could be an important component for the beneficial calcium retention in postmenopausal women.
E2 treatment also induced expression of COR1 (chemokine orphan receptor 1, RDC1), an orphan G-protein-coupled receptor (48), along with the guanylate nucleotide-binding protein 3 and the regulator of G-protein-signaling 3, suggesting that these proteins may form a functional unit. RDC1 is a receptor for the potent vasodilatory peptide adrenomedullin and calcitonin gene-related peptide, CGRP (49). Interestingly, administration of CGRP to ovariectomized rats does not produce a decrease in kidney vascular resistance; however, in ovariectomized rats treated with E2 or in pregnant rats, injection of CGRP significantly decreases kidney vascular resistance (50). The increased expression of RDC1 in the kidney seen here provides a potential mechanism for the E2 induction of sensitivity to CGRP in the kidney, potentially resulting in the large increase in renal blood flow seen during pregnancy (51).
Finally, E2 treatment reduced expression of betaine:homocysteine methyltransferase (BHMT) and S-adenosylhomocysteine hydrolase (SAHH), two enzymes involved in the methionine/homocysteine cycle (52). Elevated plasma homocysteine levels are now recognized as an important risk factor for the development of cardiovascular disease (53), and estrogen treatments reduced plasma homocysteine levels in postmenopausal women (54). Regulation of BHMT and SAHH may provide a mechanistic link between estrogens and homocysteine.
The finding of E2 regulation of numerous genes in the kidney, many of which may provide molecular links to known estrogen-regulated physiological processes, may provide new insights into the global pattern of estrogen biology. Additionally, the dependence of E2 regulation on either AF1 or AF2 mechanisms in different genes suggests that it may be possible to selectively modulate expression of various genes in the kidney through the use of selective estrogens.
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Acknowledgments |
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Footnotes |
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-hydroxylase), polypeptide 1; CYP27B1, cytochrome P450, subfamily XXVIIB (25-hydroxyvitamin D-1-hydroxylase), polypeptide 1; E2, 17ß-estradiol; ELF, E74-like factor 3; ER, estrogen receptor; ERE, estrogen response element; GADD45G, growth arrest and DNA-damage-inducible, gamma; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PPT, propylpyrazole triol; SAHH, S-adenosylhomocysteine hydrolase; SERM, selective ER modulator; STAT5, signal transducer and activator of transcription 5A; TF, tissue factor; TIM, T-cell Ig and mucin domain; WT, wild-type. Received July 18, 2002.
Accepted for publication October 16, 2002.
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) or repression (
) patterns for ER
