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NDT Advance Access published online on October 2, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm672
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Gene Expression Analysis of Kidneys From Transgenic Mice Expressing Fibroblast Growth Factor-23

Richard Marsell1, Tijana Krajisnik2, Hanna Göransson2, Claes Ohlsson3, Östen Ljunggren2, Tobias E. Larsson2 and Kenneth B. Jonsson1

1 Department of Surgical Sciences 2 Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden 3 Center for Bone Research at the Sahlgrenska Academy (CBS), Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden

Correspondence and offprint requests to: Correspondence and offprint requests to: Richard Marsell, Department of Surgical Sciences, Uppsala University Hospital, Uppsala 751 85, Sweden. Fax: +46-18-50-09-52; E-mail: Richard.Marsell{at}surgsci.uu.se



   Abstract
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 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Fibroblast growth factor-23 (FGF23), a circulating protein produced in bone, causes decreased renal inorganic phosphate (Pi) reabsorption by reducing the expression of the sodium phosphate cotransporter type 2a (Npt2a). We have previously generated transgenic mice expressing human wild-type (WT) FGF23 under the control of the {alpha}1 (I) collagen promoter.

Methods. In this study, we performed a large-scale gene expression study of kidneys from FGF23 transgenic mice and WT littermates. Microarray expression data of key transcripts were verified by real-time RT-PCR analysis.

Results. Several genes that play a role in Pi regulation revealed decreased expression levels in the transgenic mice, such as Npt2a and Pdzk1, a scaffolding protein known to interact with Npt2a. Importantly, Klotho, a suggested FGF23 receptor cofactor, was the most significantly decreased transcript and {alpha}2-Na+/K+-ATPase (Atp1a2), a gene isoform of {alpha}1-Na+/K+-ATPase (Atp1a1) which has recently been shown to interact with Klotho and regulate calcium metabolism, was the most increased transcript. In contrast, other genes proposed to regulate Pi levels, such as secreted frizzled-related protein-4 (sFrp4) and Na+/H+ exchanger regulatory factor-1 (Nherf1) revealed no changes.

Conclusions. FGF23 transgenic mice display differentially expressed transcript levels of several genes essential in renal Pi regulation. These findings may lead to further understanding of how FGF23 mediates its actions on renal Pi regulation.

Keywords: Atp1a1; Atp1a2; FGF-23; Klotho; phosphate



   Introduction
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 Introduction
Subjects and methods
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 Discussion
 References
 
Fibroblast growth factor-23 (FGF23) is a circulating protein that regulates inorganic phosphate (Pi) homeostasis. It plays a central role in several human hypo- and hyperphosphatemic disorders [1]. The importance of FGF23 in Pi homeostasis has further been demonstrated in genetically manipulated animal models that mimic these disorders [2,3]. FGF23 is produced in bone [4], secreted into the bloodstream and presumably binds to a specific FGF23-receptor in the kidney. It causes a decrease in Pi reabsorption through downregulation of the Na+/Pi cotransporters (Npt) [2] which may further result in decreased bone mineral density and rickets seen in the patients and the genetically manipulated animal models [1–3,5,6].

The Npt2a protein is expressed in renal proximal tubule brush border membrane (BBM) and it is estimated to be responsible for approximately 80% of Pi reabsorption and therefore crucial for Pi homeostasis. FGF23 decreases apical expression of Npt2a, resulting in decreased Pi reabsorption [2]. These effects are likely a result of the binding of FGF23 to a high-affinity receptor complex. Analysis of FGF23 binding to molecules in a renal homogenate has shown that FGF23 specifically binds to Klotho, a senescence-related protein [7]. Further investigations in vitro revealed that Klotho converts the FGFR1(IIIc) into a native FGF23 receptor [7]. The hypothesis that Klotho is required for FGF23 signalling is also supported by similarities in phenotypes between the Klotho and Fgf23 knock-out mice [8].

We previously generated transgenic (TG) animals that express human wild-type (WT) FGF23 under the control of the mouse {alpha}1 (I) collagen promoter [2]. Biochemical analysis of 8-week-old TG and WT animals revealed high FGF23 serum levels (7800 ± 800 RU/ml vs not detectable), hypophosphatemia (sPi 1.91 ± 0.27 mM vs 2.75 ± 0.22) and hyperphosphaturia (FEI-Pi 34.8 ± 7.6 vs 14.5 ± 2.5), hyperparathyroidism (sPTH 231 ± 62 pg/ml vs 139 ± 44), normocalcemia (sCa 2.07 ± 0.09 mM vs 2.17 ± 0.22) as well as normal 1,25(OH)2 vitamin D3 (254 ± 12 pg/ml vs 261 ± 22) and creatinine levels (55 ± 2.3 µM vs 56 ± 5.8). Further, the FGF23 TG animals develop severe osteomalacia and rickets.

In the current study, we analysed the differences in kidney gene expression between WT and these FGF23 TG mice. The aim was to find possible mediators through which FGF23 causes decreased Pi reabsorption.



   Subjects and methods
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 Subjects and methods
Results
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FGF23 transgenic mice
TG mice expressing human WT FGF23 controlled by the mouse {alpha}1 (I) collagen promoter were generated as previously described [2] and maintained in a virus- and parasite-free barrier animal facility. Mice were weaned at 18–21 days of age onto autoclaved rodent chow containing 0.75% Pi, 0.98% calcium and 1500 E/kg Vitamin D (R36, Lactamin, Stockholm, Sweden) [2]. The project was approved by the local ethics committee (approval number C 153/1).

RNA preparation
Kidneys from adult (8-week-old) WT and TG mice were surgically dissected and the tissue samples were immediately homogenised before RNA extraction according to the TRIZOL® protocol (Invitrogen, CA, USA). Total RNA was checked for purity and concentration by spectrophometer measurement (ND-1000, NanoDrop Technologies, Rocky River, OH, USA), and RNA integrity by electrophoresis on a 1% Agarose/EtBr gel. Samples were either used for global expression analysis or quantitative real-time PCR analysis. RNA samples used in real-time PCR were DNased according to manufacturer's protocol (Ambion, Cambridge, UK).

Microarray expression analysis
Total RNA from kidneys of five 8-week-old TG mice and five WT littermates were used to prepare biotinylated fragmented cRNA according to the GeneChip® Expression Analysis Technical Manual (Affymetrix Inc., Santa Clara, CA, USA). A separate expression array (GeneChip® Murine Genome U74Av2) was run for each animal. The arrays were hybridised for 16 h in a 45°C incubator, rotated at 60 rpm, then washed and stained using the Fluidics Station 400 and finally scanned using the GeneChip® Scanner GA 2500. All array experiments were performed by Swegene Microarray Resource Centre (Lund, Sweden). The data are available at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/) under the GSE series accession number GSE6979 [NCBI GEO] .

Microarray data analysis
Subsequent analysis of the gene expression data was performed in statistical computing language R (http://www.r-project.org) using packages available from the Bioconductor project (http://www.bioconductor.org). The raw data were normalised using the GCRMA method. For further analysis, we used only genes where all five mice in at least one of the groups had a ‘present’ detection call using the Affymetrix MAS5 algorithm. This resulted in a dataset containing 5689 genes. To search for the differentially expressed genes, an empirical Bayes moderated t-test was applied. To address the problem with multiple testing, the P-values were adjusted using the Benjamini and Hochberg method. To further investigate and visualise a selection of the results, hierarchical clustering was performed using the Genesis software. For the genes chosen, the distribution of Gene Ontology (GO) terms was investigated using a hypergeometric test in a GO tool [9].

Quantitative real-time PCR
The cDNA synthesis from total RNA was performed using the SuperscriptTM II Reverse Transcriptase cDNA synthesis protocol (Invitrogen, CA, USA), followed by SYBR Green quantitative real-time PCR. Each sample was run in triplicates. The quantity of mRNA was calculated based on the threshold cycle (CT) values which were standardised by the amount of the housekeeping gene. The triplicate average mouse ß-Actin CT value was subtracted from the corresponding target gene's CT-value, representing the {Delta}CT. Further calculation was performed using the 2–{Delta}{Delta}T method, always pairwise comparing the target gene with the gene of interest tested. Meltcurve and agarose gel electrophoresis analyses were performed to confirm a single product of expected length was amplified. The following primers were used: ß-Actin (Fwd 5'-ccgtaaagacctctatgcccacaacac-3'; Rev 5'-tctgtgtggatcggtggctc-3'), mNpt2a (Fwd 5'-gctgtcctcta- cctgctcgtgtg-3'; Rev 5'-gcgtgcccactccgaccatag-3'), mPdzk1 (Fwd 5'-aggtgccatagtgaacagaagac-3'; Rev 5'-cagatagaagc- catagccattgc-3'), mKlotho (Fwd 5'-tgtatgtgacagccaatggaa- tcg-3'; Rev 5'-gaatacgcaaagtagccacaaagg-3'), mLcn2 (Fwd 5'-gcctcaaggacgacaacatcatc-3'; Rev 5'-agccacactcaccaccc- attc-3').

Statistical analysis
Statistical analysis of the quantitative real-time PCR results was performed using GraphPad Prism© Version 3.03 software (GraphPad Software Inc., Australia). Differences between WT and TG groups were calculated using Student's independent t-test and presented as mean ± SEM. A P-value of <0.05 was considered statistically significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Microarray analysis
Comparison of kidney gene expression in our TG mice (n = 5) and their WT littermates (n = 5) by microarray analysis revealed many differentially expressed transcripts. In total, 87 transcripts had a P-value <0.05 and were further analysed. Out of these 87 genes, 31 genes showed decreased expression levels and 56 genes increased levels in the TG mice (Tables 1 and 2). Npt2a (Slc34a1), important for Pi reabsorption, was significantly decreased (P = 0.04), confirming previously published data [2]. Several other genes suggested as having an important role in Pi regulation also appeared in the group with decreased expression. Importantly, the Klotho gene was the most statistically significant decreased gene (P = 0.0008). Pdzk1, a gene encoding a scaffolding intracellular PDZ-domain-containing protein thought to sequester Npt2a to the apical membrane, was also decreased (P = 0.03). Another PDZ-domain-containing protein, Nherf1 (Slc9a3r1), with the previously reported ability to interact with Npt2a, showed no changes. These proteins are thought to require A-kinase anchoring proteins to create a functional complex [10]. In the present study we found A-kinase anchoring protein 1 (Akap1), with previously undescribed renal function, to be decreased (P = 0.02). However, we could not detect any changes in the gene expression of Akap2, a close family member of Akap1, previously shown to interact with Nherf1 and Pdzk1 to mediate PTH-regulating effects on Npt2a [10]. Neither did analysis of other genes encoding proteins proposed to play a key role in the regulation of serum Pi levels, such as sFrp4, Pthr1, Cyp27b1 and Fgf-receptors 1–4, reveal changes in mean value between the WT and TG groups in the gene expression data.


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  		Table 1 Of the 87 genes with a P-value ≤0.05, 31 showed decreased expression in FGF23 TG mice kidneys

 

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  		Table 2 Of the 87 genes with a P-value ≤0.05, 56 showed increased expression in FGF23 TG mice kidneys

 
In the group with increased expression, the {alpha}2-Na+/K+-ATPase (Atp1a2) (P < 0.0001) showed the most statistical significance and the highest fold change. Atp1a2 has no previously known function in Pi or calcium metabolism. Importantly, its gene isoform, Atp1a1, has recently been shown to interact with Klotho and regulate calcium homeostasis [11]. There were three Atp1a1 target sequences on the microarray. None of these showed differential expression in transcript levels between the WT and TG mice. In the increased group we also found several inflammation related genes, such as Leukotriene C4 synthase (Ltc4s), Prostaglandin E synthase (Ptges), Galactose-binding Lectin, soluble, 3 (Lgals3), Phospholipase A2 (Pla2g7) and Lipocalin 2 (Lcn2) (Table 2). Lcn2 is used as an early marker of renal damage and administration of recombinant Lcn2 to mice with renal injury markedly ameliorates the ischemic acute renal injury [12]. Furthermore, there was an increase of transthyretin (Ttr), which is used as a serum marker to measure the severity of renal damage in CKD patients [13]. None of the increased genes are known to interact with the direct regulation of Pi.

Hierarchical clustering
To further visualise the array results, we performed hierarchical clustering of the 87 most significantly altered genes. Notably, several of the most interesting decreased genes grouped closely in the analysis (Figure 1). Two subgroups, the first consisting of Npt2a and Pdzk1 and the other of Klotho and Akap1, displayed equivalent expression profiles within each group, suggesting a correlation in the regulation.


Figure 1
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  		Fig. 1 Hierarchical clustering of the 87 genes with a P-value ≤0.05. To the right is a magnification of the genes: Akap1, Klotho (Kl), Pdzk1 and Npt2a (Slc34a1). Rows indicate genes and columns indicate mice.

 
Gene ontology analysis
GO analysis was performed using a hypergeometric test with a two-sided significance level of P = 0.025. In terms of associated biological processes both the group of genes with decreased and the group with increased expression showed an over-representation of several metabolic processes. Carbohydrate and glycerol metabolism were enriched in the decreased group and lipid metabolism in the increased group. Genes important for the response to wounding and coagulation haemostasis were over-represented among the genes displaying increased expression. In terms of molecular function the decreased group showed an enrichment of cotransporters, yet none with a direct connection to Pi or calcium transport.

Quantitative real-time PCR
To verify the results obtained from the Affymetrix microarray analysis, real-time PCR analysis was performed. Kidney cDNA was produced from FGF23 TG (n = 5) and WT (n = 5) mice. The real-time PCR results showed a close stringency with the array result with reduction in expression of the genes Npt2a, Klotho and Pdzk1, respectively, in FGF23 TG mice (Figure 2). Lcn2 was used as a positive control. It showed a 9- to 10-fold increase both in the microarray and real-time PCR analysis (data not shown).


Figure 2
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  		Fig. 2 Real-time PCR results showing decreased expression of Npt2a, Klotho and Pdzk1 in TG mice compared to their WT littermates.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Herein, we show that gene expression in kidneys from FGF23 TG mice is altered compared to WT littermates. We have previously demonstrated that the FGF23 TG mouse is a model of hypophosphatemic rickets and that Npt2a expression, both at mRNA and protein levels, is decreased [2]. In the current study we corroborate these data with the Affymetrix gene expression data and it is likely that the decreased Npt2a expression is one of the most important end-results of the FGF23 signalling in the kidney. Our results are in agreement with previously published data [14].

FGF23 actions are initiated by the binding of FGF23 to a cell surface receptor. Data recently presented by Urukawa and colleagues, suggest that Klotho converts the FGFR1(IIIc) into the FGF23-receptor [7]. Our finding that Klotho gene expression is decreased by FGF23 may represent a physiological counter-regulatory mechanism to diminish FGF23 binding and signalling. Klotho expression is also decreased in kidneys from Hyp mice [15], a murine model of XLH. The Hyp mice have a mutation in the Phex gene resulting in high circulating levels of FGF23 through an unknown mechanism [16].

Interestingly, we found no changes in expression levels of FGFRs 1–4, which may indicate that the cofactor Klotho, rather than the FGFRs, regulates renal cellular response to FGF23-signalling. However, the Affymetrix analysis does not discriminate between the FGFR's b or c-isoforms. It has been reported that FGF23 shows affinity to all known c-isoforms (FGFR1–3) and also to FGFR4, but not to the b-isoforms [17]. Therefore, it is possible that the renal responsiveness to FGF23 is regulated at multiple levels.

The Early growth response-1 (Egr-1) gene has been identified as one of the immediate early response genes of FGF23-signalling [7]. It has also been shown that FGF23 induces expression of a co-repressor of Egr-1, NGFI-A-binding protein type 2 (Nab2), which decreases the transcriptional activity of Egr-1 [18]. In this study, we were not able to detect any changes in the expression of either Egr-1 or Nab2. This may be due to adaptive mechanisms in our model of chronic FGF23 overexpression.

It has been reported that Npt2a abundance in the BBM might be regulated by two intracellular PDZ-domain-containing proteins, Nherf1 and Pdzk1 [19], which co-localise with Npt2a in the BBM. Nherf1–/– mice waste Pi due to a decrease of Npt2a in BBM [20]. Further, Nherf1 has been proposed to be important in the PTH-mediated internalisation of Npt2a [21]. Whether the same mechanism is involved in FGF23-mediated effects on Npt2a has not been investigated. The analysis of our FGF23 TG mice shows differential expression levels of Pdzk1 but not of Nherf1. Pdzk1 sequesters Npt2a to the apical membrane in vitro [10] and reveal increased expression levels in kidneys from rats fed with a Pi-restricted diet [22]. Pdzk1–/– mice did not show Pi dysregulation, but when administered a high Pi containing diet Npt2a abundance was decreased [23,24]. Hence, our results indicate that Pdzk1 might have a role in the FGF23-regulation of Npt2a. Also, of interest is the decrease in Akap1 expression (P = 0.03). Akap2, a close family member of Akap1, anchors Protein Kinase A (PKA) to Pdzk1 and further interact with Nherf1 to sequester Npt2a to the BBM, suggesting involvement in PTH-regulating effects on Npt2a [10]. In the present study we could not detect any changes in Akap2, possibly implying a role of Akap1 in the regulation of Pi.

Notably, the GO analysis indicates that the gene products, with altered expression in TG animals, have an over-represented association to carbohydrate and lipid metabolism. This of interest since Fgf23 knock-out animals present with metabolic changes, such as hypoglycemia due to an increase of insulin sensitivity and glucose tolerance [25]. Further, overexpression of Klotho in mice has been proposed to have anti-aging effects due to inhibition of intracellular insulin and insulin-like growth factor-1 signalling [26]. An altered metabolism in our FGF23 TG mice could also be a secondary effect due to their hypophosphatemia, since Pi is important in several metabolic processes [27].

The array results also indicate an inflammatory reaction in the TG kidneys. In CKD patients, FGF23 is known to correlate with the severity of renal dysfunction [28]. It is not clear whether increased FGF23 levels cause primary/secondary nephritic changes or vice versa [29].

Within this study, we were not able to detect any differences in 1{alpha}-hydroxylase (Cyp27b1) mRNA expression. Thus the mRNA levels follow the same pattern as the 1,25(OH)2 vitamin D3 levels, which in our TG model is low at 4 weeks of age but normal at 8 weeks [2]. This may be due to the chronic exposure of high circulating levels of FGF23, without any treatment, and subsequent development of compensatory secondary hyperparathyroidism. However, two other FGF23 TG models that use different promoters have been described with similar phenotypical changes [5,6] but with decreased 1,25(OH)2 vitamin D3 levels also at 8 weeks of age. This may be a possible limitation to the current study, in terms of understanding the effects of FGF23 on vitamin D metabolism.

Interestingly, in a recent report, Imura and colleagues show that in a low extracellular calcium environment, there is a rapid response of PTH secretion in a Klotho/Atp1a1 dependent manner [11]. They hereby reveal a regulatory role of Klotho in calcium homeostasis. In our TG animals, the most decreased renal transcript is Klotho and the most increased is Atp1a2, a gene isoform of Atp1a1. We are not able to find any difference in transcript levels of Atp1a1 between the TG and WT mice. There has been no previous report of involvement of Atp1a2 in Pi or calcium metabolism and these data need to be further investigated.

In conclusion, this study reveals potential mediators of the Pi regulating effects FGF23 exercises in the kidney. Further analysis of these may help us understand the unraveled pathways of Pi homeostasis.



   Acknowledgments
 
This study was supported by the Genzyme Renal Investigator Program, Genzyme Corporation, the Novo Nordisk Foundation, the Swedish Research Council and the Swedish Kidney Foundation. We would like to thank Anna-Lena Johansson and Brittmarie Andersson for excellent technical assistance.

Conflicts of interest statement. Ö.L. consults for Nycomed and Lilly and received lecture fees from MSD and Amgen. T.E.L. received lecture fees. All other authors have nothing to declare.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 13. 7.07
Accepted in revised form: 3. 9.07


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