ToxSci Advance Access originally published online on December 29, 2005
Toxicological Sciences 2006 90(2):419-431; doi:10.1093/toxsci/kfj088
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Gene Expression Profiling of Nephrotoxicity from the Sevoflurane Degradation Product Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl Ether ("Compound A") in Rats
* Department of Anesthesiology, Washington University, St. Louis, Missouri 63110–1093; Department of Anesthesiology, University of Washington, Seattle, Washington 98195; and Department of Environmental Health, University of Washington, Seattle, Washington 98195
1 To whom correspondence should be addressed at Clinical Research Division, Department of Anesthesiology, Washington University, 660 S. Euclid Ave., Campus Box 8054, St. Louis, MO 63110–1093. Fax: (314) 362-8571. E-mail: kharasch{at}wustl.edu.
Received October 19, 2005; accepted December 25, 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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The major degradation product of the volatile anesthetic sevoflurane, the haloalkene fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE or "compound A"), is nephrotoxic in rats. FDVE undergoes complex metabolism and bioactivation, which mediates the nephrotoxicity. Nevertheless, the molecular and cellular mechanisms of FDVE toxification are unknown. This investigation evaluated the gene expression profile of kidneys in rats administered a nephrotoxic dose of FDVE. Male Fischer 344 rats (five per group) received 0.25 mmol/kg intraperitoneal FDVE or corn oil (controls) and were sacrificed after 24 or 72 h. Urine output and kidney histological changes were quantified. Kidney RNA was extracted for microarray analysis using Affymetrix GeneChip® Rat Expression Array 230A arrays. Quantitative real-time PCR confirmed the modulation of several genes. FDVE caused significant diuresis and necrosis at 24 h, with normal urine output and evidence of tubular regeneration at 72 h. There were 517 informative genes that were differentially expressed >1.5-fold (p < 0.05) versus control at 24 h, of which 283 and 234 were upregulated and downregulated, respectively. Major classes of upregulated genes included those involved in apoptosis, oxidative stress, and inflammatory response (mostly at 24 h), and regeneration and repair; downregulated genes were generally associated with transporters and intermediary metabolism. Among the quantitatively most upregulated genes were kidney injury molecule, osteopontin, clusterin, tissue inhibitor of metalloproteinase 1, and TNF receptor 12, which have been associated with other forms of nephrotoxicity, and angiopoietin-like protein 4, glycoprotein nmb, ubiquitin hydrolase, and HSP70. Microarray results were confirmed by quantitative real-time PCR. FDVE causes rapid and brisk changes in gene expression, providing potential insights into the mechanism of FDVE toxification, and potential biomarkers for FDVE nephrotoxicity which are more sensitive than conventional measures of renal function.
Key Words: sevoflurane; compound A; nephrotoxicity; haloalkene; microarray; kidney injury molecule.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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The haloalkene fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, referred to as "compound A" in the drug label) results from the degradation of the volatile anesthetic sevoflurane in anesthesia machines by carbon dioxide absorbents which contain strong base (Frink et al., 1992
; Hanaki et al., 1987). FDVE causes proximal tubular necrosis in rats when administered by inhalation or intraperitoneal injection (Keller et al., 1995; Kharasch et al., 1997, 1998; Morio et al., 1992). Necrosis is accompanied by increased serum creatinine, diuresis, and urinary excretion of protein, glucose, and renal tubular enzymes. In rats, FDVE undergoes a complex route of metabolism and bioactivation, which mediates the nephrotoxicity (Altuntas et al., 2004; Anders, 2005; Iyer and Anders, 1996, 1997; Iyer et al., 1998; Jin et al., 1995, 1996; Sheffels et al., 2004; Spracklin and Kharasch, 1996; Tong and Anders, 2002; Uttamsingh et al., 1998). FDVE reacts with glutathione to form glutathione conjugates, which undergo cleavage to the corresponding cysteine S-conjugates, which may undergo N-acetylation to form nontoxic mercapturates, which are excreted in urine. Reactive intermediates may be formed via the metabolism of FDVE cysteine S-conjugates and by the sulfoxidation FDVE of cysteine S- or mercapturic acid conjugates.
Although the metabolism of FDVE is well-characterized, the mechanism of nephrotoxicity is poorly understood. Like many other nephrotoxic haloalkenes, renal cysteine conjugate ß-lyase-catalyzed metabolism of FDVE cysteine S-conjugates, and sulfoxidation of mercapturates, are thought to mediate nephrotoxicity in rats in vivo (Altuntas et al., 2003, 2004; Anders, 2005; Iyer et al., 1997; Kharasch et al., 1997, 1998; Sheffels et al., 2004). FDVE cysteine S-conjugates metabolism by renal ß-lyase forms reactive intermediates (thiolate and thioacyl fluoride) (Tong and Anders, 2002); however, it is not known if, or how, they contribute to FDVE renal toxicity in vivo. Certain FDVE S-conjugates sulfoxides are also highly reactive (Sheffels et al., 2004) and toxic in vitro (Altuntas et al., 2003), but their potential role in toxicity in vivo is similarly unknown. Other haloalkenes S-conjugates also undergo ß-lyase-mediated metabolism to reactive intermediates (thioacyl halides, thioketenes) (Anders, 2004), and form adducts with renal proteins and other macromolecules which are thought to participate in toxification (Anders, 2004). Mitochondria are a major target of several haloalkene S-conjugates in isolated renal cells (Lash et al., 2000); however, it is unknown if they are a target of FDVE cysteine S- or mercapturic acid conjugates. In addition to protein alkylation and mitochondrial dysfunction, other postulated mechanisms of haloalkene cytotoxicity include oxidative stress, calcium ion dysregulation, apoptosis, and altered expression of genes regulating cell growth and differentiation (Lash et al., 2000, 2001, 2003). It is unknown whether any of these pathways are operant in FDVE toxicity.
In humans, FDVE undergoes qualitatively similar biotransformation to glutathione and cysteine S-conjugates (Altuntas and Kharasch, 2001, 2002; Altuntas et al., 2004; Iyer and Anders, 1996; Iyer et al., 1998; Kharasch and Jubert, 1999). Nevertheless, exposure of surgical patients to FDVE during sevoflurane anesthesia has been found to have no clinically significant effects (Bito and Ikeda, 1996; Conzen et al., 2002; Fukuda et al., 2004; Higuchi et al., 1998; Kharasch et al., 2001, 2003; Obata et al., 2000). These clinical investigations have evaluated the conventional markers of serum creatinine and urea nitrogen, and also proteinuria, glucosuria, and enzymuria. Nevertheless, there is concern about the sensitivity of the conventional clinical measures of renal function and considerable effort to identify more sensitive markers of renal toxicity in humans (Hewitt et al., 2004).
Toxicogenomics holds promise for elucidating cellular mechanisms of xenobiotic renal toxification, identifying potential site-specific biomarkers of toxicity, which could afford greater sensitivity, earlier detection, and/or quantitative estimates of tissue injury, and for forecasting potential candidate protein biomarkers (Bailey and Ulrich, 2004; Hayes and Bradfield, 2005; Thukral et al., 2005). Gene expression profiles have been generated for ischemic renal injury and several renal toxins known to act via diverse pathways, with the emergence of some expression profiles for generalized renal nephrotoxicity and for toxin-specific injury (Amin et al., 2004; Basile et al., 2005; Davis et al., 2004; Devarajan et al., 2003; Goodsaid, 2004; Huang et al., 2001; Kramer et al., 2004; Lühe et al., 2003; Thompson et al., 2004; Thukral et al., 2005). The purpose of this investigation was to evaluate the gene expression profile of kidneys in rats exposed to doses of FDVE that are known to cause nephrotoxicity.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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Animal treatments.
Fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE, 99.92% purity) was provided by Abbott Laboratories (Abbott Park, IL). RNAlater and the RNeasy mini kit were purchased from Qiagen (Valencia, CA). GeneChip® Rat Expression Array 230A arrays were purchased from Affymetrix (Santa Clara, CA). All experiments were approved by the University of Washington Animal Care and Use Committee and conducted in accordance with American Association for Accreditation of Laboratory Animal Care guidelines. Male Fischer 344 rats (12 weeks, 225–275 g) were purchased from Harlan (San Diego, CA). Rats were housed in individual metabolic cages, acclimated for at least 48 h prior to any experiments, provided food and water ad libitum, and maintained on a 12-h light-dark cycle (7 A.M. to 7 P.M.). The FDVE dose used in these experiments (0.25 mmol/kg) was based on the threshold dose for nephrotoxicity observed in previous experiments (Kharasch et al., 1997
). Twenty rats were randomized to one of four treatment groups (n = 5 per group): no treatment, corn oil (24 h), FDVE (24 h), or FDVE (72 h). No-treatment controls were euthanized 48 h after transfer to the metabolic cages. Corn oil controls received 2 ml/kg corn oil and were euthanized 24 h later. FDVE rats received 0.25 mmol/kg in corn oil by intraperitoneal injection and were euthanized 24 or 72 h later. Urine was collected in 24-h intervals. Rats were anesthetized with pentobarbital and sacrificed by cardiac exsanguination. Kidneys were immediately excised, cut in a midtransverse plane through cortex and medullary pyramid, and a section fixed in 10% neutral buffered formalin. Sections were stained with hematoxylin and eosin and periodic acid-Schiff, and histologic analysis was performed by a veterinary pathologist blinded to animal treatments. Histopathologic changes were recorded in regard to location, character, and severity. The semiquantitative severity score consisted of a range from 0 to 4 (normal, minimal, slight, moderate and marked, respectively), which reflected the degree and distribution of the tubular necrosis.
Microarrays.
The remainder of the kidney was saved in RNAlater and stored at –20° C for future processing. RNA was extracted from 10 to 25 mg of kidney tissue using the RNeasy Mini kit (Qiagen Inc, Valencia, CA) according to the manufacturer's directions except as follows: Tissue disruption was performed in an ice-cold Teflon-glass homogenizer with 600 µl of RNeasy lysis buffer. This was followed by further homogenization through a 20-g needle with a 1-ml syringe. Subsequent procedures followed the manufacturer's directions for RNA extraction from animal tissues. RNA labeling, gene chip hybridizations, and gene chip scans were conducted at the University of Washington Center for Expression Arrays. Each total RNA sample was evaluated for quality on an Agilent 2100 bioanalyzer, then converted into biotin-labeled cRNA using the Affymetrix eukaryotic target labeling protocol (www.affymetrix.com). Briefly, 5 µg of total RNA was reverse transcribed to double-stranded cDNA via a round of transcription with Superscript II and then a round with T4 DNA polymerase. The resulting cDNA was converted to biotinylated cRNA in the presence of T7 DNA polymerase and biotin-labeled nucleotides. This resulting cRNA was fragmented and used for hybridization to an Affymetrix Rat 230A GeneChip according to standard Affymetrix protocols. The 230A chip contains 30,248 transcripts for 28,757 genes.
Quantitation of specific gene expression.
Quantitation of mRNA levels for specific genes was accomplished by real-time quantitative PCR with a fluorogenic 5' nuclease-dependant (TaqMan®-based) quantitative gene expression assay using an ABI (Applied Biosystems Inc., Foster City, CA) iScience 7900HT Fast Real-Time PCR System, as described previously (Diaz et al., 2001; Kevil et al., 2004; Lin et al., 2002). PCR primers and probes (Table 1) were selected using Primer Express 1.5® software supplied by ABI. The sequences of each gene were taken from Affymetrix's NetAffx® Analysis Center (www.Affymetrix.com). A reference standard was identified by evaluating similar sample types for high mRNA expression of GAPDH. After an appropriate reference standard was established, this sample was serially diluted to derive a linear regression formula that was used to calculate and quantitate specific gene expression. The levels of mRNA expression of the GAPDH gene were used to normalize these data. The PCR mixture (20 µl final volume) for this assay consisted of the appropriate sense and antisense primers (0.35 µM each), 100 nM TaqMan probe, and 1x TaqMan® Fast Universal PCR Master Mix (Applied Biosystems, Inc.). Amplification and detection of fluorescence was measured using the ABI 7900 system with the following PCR reaction profile: 1 cycle of 95°C for 15 s, 40 cycles of 95°C for 1 s, and 60°C for 20 s.
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Data analysis.
Image processing and expression analysis were performed using Affymetrix GeneChip Operating Software (GCOS). Each GeneChip image underwent GCOS absolute expression analysis. The quality of the hybridizations and overall chip performance were determined by visual inspection of both the raw scanned data and the extracted quality control metrics, including performance of spike-in controls and endogenous housekeeping genes (Actin and GAPDH). The resultant cell intensity files (CEL) were analyzed by the University of Washington Center for Ecogenetics and Environmental Health: Bioinformatics and Biostatistics Core. Microarray data are available online. (Add link to supplementary data here) Statistical analysis and data normalization were carried out with: GeneTraffic® (Iobion Informatics LLC, La Jolla, CA) and Bioconductor software developed by collaborators based at the Biostatistics Unit of the Dana Farber Cancer Institute at Harvard Medical School/Harvard School of Public Health [http://bioconductor.org] (Gentleman et al., 2004
). These software packages were used to hierarchically cluster the data and evaluate the data statistically and qualitatively. Each data set consisted of five replicates, with each replicate corresponding to a single animal. Data normalization was performed in Genetraffic® using a modified version of the Robust Multi-Array method (Irizarry et al., 2003), called the GC-RMA method (Wu et al., 2004), which uses the GC content of the mismatch probes for a better background adjustment of the perfect match probes.
Statistical analysis was performed with Genetraffic® to evaluate increases or decreases in gene expression using an unpaired two class t-test with the Benjamini-Hochberg correction for multiple comparisons (Benjamini and Hochberg, 1995). Results for comparison pairs are expressed as a fold change. Statistical significance was assigned at a minimum 1.5-fold change and p < 0.05. No significant differences in gene expression were found between the untreated and corn oil–treated rats; thus the corn oil–treated rats were used as the controls for all subsequent analyses. Data sets compared were FDVE (24 h) versus corn oil, FDVE (72 h) versus corn oil, and FDVE (24 h) versus FDVE (72 h).
RT-PCR results are expressed as the mean ± SD. Data were analyzed by analysis of variance, and significance assigned at p < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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Effects of FDVE on animal weight, urine output, and renal tubular necrosis are provided in Table 2. Significant necrosis was observed in rats given FDVE, and evidence of tubular regeneration was observed at 72 h. Significant diuresis was also observed, with return to control values at 72 h. One animal in the 72-h group was less affected (see below) that the others in this group (24, 48, and 72-h urine output was 10, 10, and 8 ml, compared with means of 29, 16, and 13 ml in the other four animals; renal necrosis was scant, compared with a median of 3 in the other four animals). In the remaining animals, renal effects were similar to those seen previously at this intraperitoneal dose (Kharasch et al., 1997
; Sheffels et al., 2004) and at approximately 350–400 ppm-h inhaled FDVE (Keller et al., 1995; Kharasch et al., 1998). Previous studies have also shown that FDVE renal effects were greatest after 24 h (diuresis and osmolality) or 48 h (proteinuria), with recovery apparent at 72 h (Kharasch et al., 1997, 1998; Sheffels et al., 2004).
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Data were evaluated first for the qualitative amount of differential gene expression (fold change). The following comparisons were performed: 24 h versus corn oil baseline (24-h data set), 72 h versus corn oil baseline (72-h data set) and 24 versus 72 h with 72-h values as baseline (24 vs. 72-h data set). Each data set consisted of an expression array from each of five animals. A current consensus uses a filter criterion of genes that are up- or downregulated two-fold or greater. However, due to the number of replicates and the agreement between them, we felt confident in using a 1.5-fold change in expression as the threshold to filter these three data sets. Using this criterion, the 24-h data set had 795 genes that were differentially expressed versus controls by at least 1.5-fold, with 414 genes upregulated and 381 downregulated. The 72-h data set had a total of 490 genes, with 274 up- and 216 downregulated. The 24-h versus 72-h data set had a total of 381 genes that were differentially expressed, with 179 upregulated and 202 downregulated. The resulting lists of genes for each data set were further evaluated for statistical significance using an unpaired two-class t-test with an adjusted p value < 0.05 and the Benjamini-Hochberg method to correct for multiple hypothesis testing and prevent false positives. This provided a final list of 544 informative genes with a fold change in expression of 1.5 or greater and p < 0.05 in one or more of our data sets.
An unsupervised hierarchial cluster analysis was performed on this list of 544 genes (Fig. 1). Samples clustered according to treatment and time, except for one FDVE-treated rat at 72 h which clustered with the corn oil controls. Clustering reflected the renal injury. The FDVE-treated animal which clustered with the controls was the one which showed substantially less necrosis and urine output (see above). Overall, 72-h results showed greater interindividual variability than the 24-h values, which may reflect inherent variability in the capacity to recover from FDVE.
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The overall list of 544 genes with
1.5-fold change and p < 0.05 was further analyzed for group comparisons. The 24-h FDVE versus control data set had 517 genes (of which 234 were upregulated and 283 were downregulated), the 72-h FDVE versus control data set had no genes, and the 24-h FDVE versus 72-h FDVE set had 127 genes (of which 72 were upregulated and 50 were downregulated at 72 h compared with 24 h, Tables 3 and 4). These are not independent lists of genes (Fig. 2). Of the 127 genes that vary significantly between the 24- and 72-h time points, 97 were also in the 517-gene group which was significantly different at 24 h versus control, suggesting that these 97 genes were returning to control values at 72 h. This leaves 27 unique genes that vary at 72 h but not 24 h. The lack of statistical significance between the 72-h FDVE versus corn oil data set appeared at variance with the degree of gene modulation and was thought to be due to the 72-h FDVE-treated animal that clustered with the controls, and the resulting group variance leading to lack of statistical significance. Therefore, a reanalysis of the 72-h FDVE versus corn oil and the 24-versus 72-h data was performed with omission of the one outlier, described above, in the 72-h FDVE group. After omitting this sample, the 72 h FDVE data set had 175 genes that were differentially expressed 1.5-fold versus controls, with 91 upregulated and 84 downregulated, and the 24- versus 72-h data set had 104 differentially expressed genes (56 upregulated and 48 downregulated). Of the 517 genes that varied significantly at 24 h, 75 are significantly different at 72 h versus 24 h, indicating their return to control, while 175 remained significantly different versus control.
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Further analysis of the 24 h data set was performed. Differentially regulated genes were grouped into major functional categories. To limit the size of the candidate gene set, inclusion in the table was based on a 3-fold upregulation (Table 3) or downregulation (Table 4) at 24 h. For comparison, fold-changes at 72 h are also included. Predominant classes of upregulated genes included those involved in apoptosis, oxidative stress, inflammatory response, and regeneration and repair; downregulated genes were generally associated with transporters and enzymes of intermediary metabolism. Genes associated with phase 1 xenobiotic metabolism (cytochrome P450) were downregulated, while those associated with phase 2 metabolism were upregulated. Among the quantitatively most upregulated genes were kidney injury molecule, angiopoietin-like protein 4, osteopontin, glycoprotein nmb, ubiquitin hydrolase, clusterin, and TNF receptor. Several other genes, yet unidentified, were also significantly upregulated.
Additional classification of groups of differentially expressed genes based on the Gene Ontology was performed using the GenMAPP program (Doniger et al., 2003). Since the rat genome is less annotated than some others, only 236 of the 517 genes were recognized by GenMAPP. The top 20 Gene Onotology categories for up- and downregulated genes at 24 h, ranked according to z score, are listed in Table 5.
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Microarray results were confirmed for a subset of genes using quantitative real-time PCR (Table 6). A selected set of up- and downregulated genes, of varying fold change, was evaluated. RT-PCR confirmed the upregulation of kidney injury molecule, HSP70, clusterin, osteopontin, and TNF receptor 12 at 24 h after FDVE, which were identified by microarray. Consistent with the microarray results, kidney injury molecule was the most quantitatively upregulated. RT-PCR also confirmed the downregulation of organic anion transporter 1 (solute carrier family 21, member 1), histamine N-methyltransferase, chronic renal failure gene, and regucalcin at 24 h, which continued to be downregulated at 72 h.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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The results of this investigation demonstrate that a dose of FDVE which results in structural and functional evidence of nephrotoxicity also causes a marked alteration in renal gene expression profiles in Fischer 344 rats. This is the first investigation profiling renal gene expression following a nephrotoxic fluoroalkene. Only one other investigation has reported the renal expression profile in rats following a nephrotoxic haloalkene, specifically the chloroalkene hexachlorobutadiene (Thukral et al., 2005
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It is likely that the expression pattern of genes upregulated at 24 and 72 h after FDVE administration reflects both pathways of toxification (apoptosis, oxidative stress, and/or necrosis) and response to injury (inflammation, regeneration, and repair). Upregulation of genes subtending apoptosis and especially oxidative stress (UCHL1, HSPs, heme oxygenase, glutathione peroxidase, NADPH dehydrogenase) was generally greater at 24 h compared with 72 h, consistent with greater impairment of renal function at this time point and a potential association with mechanisms of FDVE toxification. The relatively small number of apoptotic genes upregulated at 24 h may be interpreted as a relative lack of involvement of apoptosis in FDVE toxicity, or an indication that these are early response genes whose upregulation is diminished by 24 h. Previous investigations with the cysteine S-conjugates of the nephrotoxin trichloroethylene showed that apoptosis occurred much earlier than necrosis and at lower concentrations (Chen et al., 2001; Lash et al., 2001, 2003). Additional studies, evaluating earlier time points, are needed to resolve the role of apoptosis in FDVE toxicity. Genes subtending inflammation, regeneration, and repair were already upregulated at 24 h and were generally persistently elevated (Kim-1, osteopontin, GPNMB, clusterin, galectin, fibrinogen, calpectin, calcyclin), if not even more greatly expressed (CD44) at 72 h, while others had returned to near control values. This is consistent with the histologic evidence of regeneration which was observed at 72 h. It is also consistent with the early occurrence of renal tissue repair observed after exposure to the S-conjugates of other nephrotoxic haloalkenes (Vaidya et al., 2003a,b). Tissue repair processes are a major determinant of the progression of renal injury after S-conjugate toxicity and influence whether acute injury is followed by restoration of renal tubular structural and functional integrity or by irreversible massive necrosis, renal failure, and death (Vaidya et al., 2003a,b). Hence, expression of regeneration and repair genes signals not only renal injury, but also renal repair. Upregulation of inflammatory genes may be predictive of downstream events; however, additional studies evaluating later time points would be needed to for verification. In contrast to upregulation, downregulation of gene expression after FDVE generally persisted through the 72-h observation period.
The renal expression profile following FDVE administration bears strong similarity to that following exposure to several other nephrotoxins, which has been observed both in rodents and in nonhuman primates. Recent investigations have demonstrated a suite of renal genes which are modulated in vivo in response to injury caused by a diverse group of model nephrotoxins, including cisplatin (Amin et al., 2004; Huang et al., 2001), gentamycin (Amin et al., 2004; Davis et al., 2004), puromycin (Amin et al., 2004; Thukral et al., 2005), ochratoxin (Lühe et al., 2003), and mercuric chloride, 2-bromoethylamine hydrobromide, hexachlorobutadiene, mitomycin, and amphotericin (Thukral et al., 2005). Genes highly (more than five-fold) and significantly upregulated rather consistently include glutathione transferase pi, Kim-1, osteopontin, tissue inhibitor of metalloproteinase 1 (TIMP1), clusterin, vimentin, and fibrinogen alpha, and those also upregulated but less so (typically two- to five-fold) include heme oxygenase, UDP-glucuronosyltransferase, glutathione synthetase, insulin-like growth factor binding protein 1 (IGFBP1), and annexinA7. Genes significantly downregulated more than five-fold generally include regucalcin and several organic ion transporters, including organic anion transporter protein 1(SLC21A1/OATP1), organic anion transporter family member 1A2 (SLC21A7/OATP3), and solute carrier family 22 (organic cation transporter) member 2 (SLC22A2/OCT2), and those also downregulated but less so (typically two- to five-fold) include solute carrier family 22 member 6 (organic anion transporter 1, SLC22A6/OAT1) and HSP27. Like those modulated after FDVE, these also tend toward genes involved in tissue regeneration and inflammation, which frequently occur as a consequence of necrosis, and which have been associated with tissue repair after various forms of acute renal failure (Huang et al., 2001; Thukral et al., 2005). One recent investigation of rat gene expression evaluating dose-response effects of several model nephrotoxins showed some clustering of expression profiles according to the degree of injury, which was independent of the specific nephrotoxin (Thukral et al., 2005). Milder forms of injury causing degeneration/regeneration resulted in upregulation of glutathione S-transferase P1, Kim-1, osteopontin, and TIMP1 and downregulation of OATP1, while more severe toxicity causing necrosis resulted in upregulation of these and several other genes and downregulation of several more transporters (Thukral et al., 2005). While most of the organic ion transporters were downregulated after FDVE, solute carrier family 34 (sodium phosphate), member 2 (SLC34A2) was upregulated, a finding similar to that after several other nephrotoxins (Thukral et al., 2005). Interesting exceptions to the pattern of renal injury response genes frequently upregulated after acute renal injury were vimentin and insulin-like growth factor binding protein 1 (IGFbp1), which were only increased by FDVE 1.4- and 1.9-fold, respectively, at 24 h (not shown).
Expression profiling was a much more sensitive indicator of FDVE renal effects than more conventional measures of renal function. Whereas similar (0.25–0.3 mmol/kg) FDVE doses caused negligible or small (two-fold) changes in serum creatinine and urea nitrogen, and urine protein excretion (Kharasch et al., 1997; Sheffels et al., 2004), expression of several genes was modulated at least 5-fold (clusterin, TIMP1, TNFRSF12, CFTR/MRP, heme oxygenase, histamine N-methyltransferase, organic ion transporters), others at least 10-fold (osteopontin, ANGPTL4, GPNMB, UCHL1, organic ion transporters), and Kim-1 was upregulated approximately 100-fold. These results suggest that one or more of these modulated genes may serve as an early and sensitive biomarker for FDVE toxicity. Characteristic or predictive candidate biomarkers for nephrotoxicity identified most consistently in other investigations include the genes for Kim-1, osteopontin, and clusterin, and others identified by some as potentially useful include IGFBP-1, alpha-fibrinogen, GSTalpha, lipocalin, TNF receptor 12a, and several transporters (SLC21a2, SLC15, SLC34a2) (Amin et al., 2004; Davis et al., 2004; Thukral et al., 2005).
Kim-1 was the gene most consistently and quantitatively upregulated in response to FDVE, as well as by several other nephrotoxins. FDVE stimulated Kim-1 gene expression 254-fold over control at 24 h, and at 72 h this gene was still upregulated more than 100-fold. In a nonhuman primate model of antibiotic nephrotoxicity, quantitative analysis showed that Kim-1 had the greatest increase in gene expression among various biomarkers (Davis et al., 2004). Kim-1 is a type 1 membrane glycoprotein with a large ectodomain containing immunoglobulin and glycosylated mucin subdomains and a short cytoplasmic tail. Kim-1 constitutive expression is low, but upregulated in association with dedifferentiated and regenerating tubular epithelial cells (Han et al., 2002). Increased Kim-1 protein expression in proximal tubule epithelial cells of kidneys from rats treated with the haloalkene conjugate S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (TFEC) was shown by immunoblotting, immunofluorescence, and immunohistochemistry, and the Kim-1 soluble protein ectodomain and fragments were demonstrated in urine by immunoblotting (Ichimura et al., 2004). The Kim-1 ectodomain is cleaved by matrix metalloproteinases and shed into cell culture media and into urine following experimental nephrotoxicity and ischemia/reperfusion in rats and acute tubular necrosis in humans (Bailly et al., 2002; Han et al., 2002; Ichimura et al., 1998, 2004). The specific role of Kim-1 is unknown, but its expression in dedifferentiated cells in response to several renal ischemic and toxic insults suggests that it is important in repair processes involving dedifferentiation, migration, proliferation, and restoration of cellular architecture and function (Ichimura et al., 2004). Early expression of Kim-1, and its detectability at degrees of injury at which conventional renal markers do not change, has resulted in the conclusion that Kim-1 may be a sensitive biomarker for mild–moderate renal injury and repair. The results in the present investigation are consistent with that hypothesis. It remains unknown whether Kim-1 protein is expressed in kidneys or excreted in urine following FDVE nephrotoxicity.
Osteopontin expression is upregulated following several forms of toxic renal injury, not limited to the proximal tubule (Amin et al., 2004; Basile et al., 2005; Davis et al., 2004). It is a chemoattractant for macrophages and also inhibits apoptosis. Osteopontin is constitutively secreted in urine and has been shown to be secreted in increased amounts in at least one model of nephrotoxicity (Khan et al., 2002). Clusterin gene expression is also upregulated in response to numerous forms of renal toxicity, remodeling, and diseases (Amin et al., 2004; Davis et al., 2004). The role of clusterin in renal injury and regeneration is unknown, but clusterin is detectable in urine before changes in serum creatinine after renal injury and has been suggested as a potential biomarker. Upregulation of osteopontin and clusterin gene expression following FDVE nephrotoxicity is consistent with a role as a potential biomarker.
Upregulation of sterol metabolism genes was observed directly in the microarray analysis and was reflected also in the Gene Ontology categories for biological processes (sterol metabolism) and molecular functions (hydroxymethylglutaryl-CoA synthase activity). Renal cortical cholesterol accumulation is a prominent feature after acute renal toxicity, postulated as an adaptive response, and due in part to increased renal tubular cell cholesterol synthesis (Zager et al., 2002).
Less well understood are the mechanisms and implications of gene downregulation following FDVE and other nephrotoxic injuries. Downregulation of several organic ion transporters by FDVE is consistent with previous effects of several other nephrotoxins (Amin et al., 2004; Davis et al., 2004; Thukral et al., 2005). Downregulation of histamine-N-methyltransferase expression is an interesting observation. Inhibition of histamine-N-methyltransferase by metoprine resulted in brisk diuresis and decreased urine osmolality, by an unknown mechanism (Lecklin et al., 1999). It is unknown whether metoprine resulted in renal cellular toxicity, or whether histamine-N-methyltransferase plays a role in the diuresis and decreased urine osmolality following FDVE. Another interesting observation is the identification of meprin activity, and that of its parent family astacin, as downregulated Gene Ontology functional categories. Microarray analysis showed that meprin was downregulated 2.8-fold (not shown). Meprins are metalloproteases highly expressed at the brush border membrane of renal proximal tubular cells and cleave a wide variety of substrates, including cytokines such as osteopontin (Bond and Beynon, 1995; Bond et al., 2005). Meprins can be detrimental when there is renal tissue damage and are downregulated in renal injury and in situations leading to cell death through apoptosis or necrosis. Upregulation of TIMP1, chemokines, and osteopontin observed directly on the microarrays is consistent with the Gene Ontology identification of meprin downregulation. The role of meprins and metalloproteases in the pathogenesis of or response to FDVE nephrotoxicity merits evaluation. Downregulation of regucalcin by FDVE is similar to that reported recently in response to another nephrotoxin (Thukral et al., 2005). The physiologic role of regucalcin, found in renal cortex but not medulla, is incompletely elucidated, but this protein may play a role in regulating intracellular calcium homeostasis, suppress DNA synthesis, participate in protein degradation, and suppress apoptosis and cell death, and suppression of expression has been suggested to cause renal tubular cell dysfunction (Nakagawa and Yamaguchi, 2005; Yamaguchi, 2005). The toxicologic implication of regucalcin downregulation by FDVE requires further investigation. Downregulation of chronic renal failure gene (nucleolar GTP-binding protein 1) was confirmed by RT-PCR; however, the mechanism and implications of this modulation are unknown.
In summary, FDVE nephrotoxicity was associated with rapid and brisk changes in gene expression. Upregulation of genes involved in apoptosis, oxidative stress, and inflammatory response may provide potential insights into the mechanism of FDVE toxification. A suite of upregulated genes, including kidney injury molecule, osteopontin, clusterin, tissue inhibitor of metalloproteinase 1, and TNF receptor 12, have also been associated with other forms of nephrotoxicity. Gene expression profiling may provide potential biomarkers for FDVE nephrotoxicity which are more sensitive than conventional measures of renal function. Gene expression profiling may provide potential biomarkers for evaluating the clinical effects of FDVE exposure in humans.
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SUPPLEMENTARY DATA |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAREFERENCES |
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Supplementary data are available online at http://toxsci.oxfordjournals.org/.
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ACKNOWLEDGMENTS |
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The authors appreciate the excellent assistance of Dr. Mette Peters, UW Center for Expression Arrays. Supported by NIH grants R01DK53765, 5U24DK058813 and NIEHS P30ES07033 to the Center for Ecogenetics and Environmental Health.
Conflict of Interest Statement: No author has any conflict of interest. Evan Kharasch formerly served as an occasional ad hoc consultant to Abbott Laboratories, which markets sevoflurane.
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