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NDT Advance Access originally published online on January 25, 2005
Nephrology Dialysis Transplantation 2005 20(3):539-544; doi:10.1093/ndt/gfh673
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Original Article

Up-regulation of TRAIL mRNA expression in peripheral blood mononuclear cells from patients with minimal-change nephrotic syndrome

Shin Okuyama, Atsushi Komatsuda, Hideki Wakui, Namiko Aiba, Naohito Fujishima, Keiko Iwamoto, Hiroshi Ohtani and Ken-ichi Sawada

Third Department of Internal Medicine, Akita University School of Medicine, Akita, Japan

Correspondence and offprint requests to: Atsushi Komatsuda, MD, Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543, Japan. E-mail: komatsud{at}med.akita-u.ac.jp



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Minimal-change nephrotic syndrome (MCNS) is considered to be associated with T-cell dysfunction and with the abnormal secretion of putative glomerular permeability factors; however, the nature of such factors remains elusive.

Methods. To identify up-regulated genes during the nephrosis phase, we undertook serial analyses of gene expression (SAGE) in peripheral blood mononuclear cells (PBMC) from a patient with MCNS sampled during the nephrosis and remission phases. To confirm the SAGE results, we performed quantitative real-time reverse transcription–polymerase chain reaction (RT–PCR) analyses. We also measured the serum levels of the identified gene product in nephrosis and remission samples from 29 MCNS patients, 57 patients with nephrotic syndrome due to other types of glomerular diseases and 30 healthy individuals.

Results. Using more than 20 000 SAGE tags, we identified 15 functionally known genes that were up-regulated (≥4-fold) in PBMC from the MCNS patient during the nephrosis phase. For further examination, we selected two genes encoding secretory proteins, namely tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and tissue inhibitor of metalloprotease 1. Real-time RT–PCR analysis confirmed a higher expression of TRAIL mRNA in PBMC during nephrosis than during remission in eight MCNS patients. The expression pattern of TRAIL mRNA, however, was variable among four patients with membranous nephropathy. There was no significant increase of serum levels of a soluble form of TRAIL in MCNS patients during the nephrosis phase.

Conclusions. These results suggest that the intracellular TRAIL mRNA expression in PBMC is up-regulated in MCNS patients during the nephrosis phase. This change may represent either an epiphenomenon or it may provide a potential explanation for the altered T-cell function in MCNS.

Keywords: gene expression profile; minimal-change nephrotic syndrome; serial analysis of gene expression; tumour necrosis factor-related apoptosis-inducing ligand



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Minimal-change nephrotic syndrome (MCNS) is a clinicopathological entity defined by selective massive proteinuria, and a relapsing and remitting course, without histological evidence of classic immune-mechanism mediated injury [1]. MCNS is considered to be associated with T-cell dysfunction. Abnormal soluble factors produced by activated T-cells might alter the permeability of the glomerular filtration barrier [1]. In fact, experimental studies have shown that peripheral blood mononuclear cells (PBMC) and T-cell hybridomas derived from patients with MCNS could produce proteinuria-inducing factors in rats [2,3]. Pegoraro et al. [4] also demonstrated that serum from patients with MCNS altered the albumin permeability of monolayers of cultured rat glomerular epithelial cells. Circulating humoral factors are, therefore, likely to have important roles in the pathogenesis of MCNS. Although the nature of these factors remains elusive, several studies have suggested that cytokines, such as interleukin-2 and interferon (IFN)-{gamma}, are involved in the development of MCNS [5 and references therein].

Recently, Sahali et al. [6], screening a library of subtracted cDNA, reported on a novel approach for the identification of PBMC genes that are potentially involved MCNS relapse. Their preliminary screening of the library, with relapse and remission unsubtracted cDNA probes, identified approximately 1000 clones. They finally found 42 up-regulated known transcripts in MCNS relapse. These transcripts included genes encoding proteins associated with signalling pathways and the cytoskeletal scaffold.

Serial analysis of gene expression (SAGE), a recently developed functional genomic approach, has enabled us to identify simultaneously the expression pattern of thousands of genes [7]. Therefore, SAGE can be applied for comparing differences of gene expression between PBMC from MCNS patients during the nephrosis and remission phases. In the present study, we capitalized on an advantage of SAGE for screening of mRNA expression in PBMC from a MCNS patient during the two phases. Among the up-regulated genes in the nephrosis sample, two were for secretory proteins, namely tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (approved gene symbol TNFSF10) [8,9] and tissue inhibitor of metalloprotease 1 (TIMP-1). We selected these genes for further examinations.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Patients
The one patient selected for construction of a SAGE library was a 42-year-old Japanese woman, Patient 1, who visited us with acute onset of nephrotic syndrome on 6 December 2001. On physical examination, she had oedema in the legs and a blood pressure of 168/98 mmHg. Her urinalysis was 3+ positive for protein without haematuria. Her total 24-h urinary protein was 12.5 g, serum total protein 4.9 g/dl, albumin 2.2 g/dl, blood urea nitrogen 7.1 mg/dl, creatinine 0.6 mg/dl, creatinine clearance 106.8 ml/min, leukocyte count 11 200/µl, haemoglobin 13.2 g/dl and platelet count 34.1 x 104/µl. Her serum immunoglobulins were normal and her anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies and cryoglobulins were negative. Serum complement C3 was 193 mg/dl, C4 23.5 mg/dl and CH50 42.5 U/ml. Circulating immune complexes were not detected by the C1q-binding assay. Serum and urine electrophoresis showed no monoclonal proteins. A renal biopsy revealed minimal changes in 16 glomeruli, without mesangial proliferation, interstitial cell infiltration or focal segmental glomerulosclerosis (FSGS). Immunofluorescence stainings for immunoglobulin (Ig)-G, IgA, IgM, {kappa}, {lambda}, C3, C1q and fibrinogen yielded negative results.

Based on these findings, she was diagnosed to have MCNS and was treated with prednisolone (40 mg/day). With the treatment, she reached complete remission within 2 weeks. While her dosage of prednisolone was being tapered, her MCNS relapsed. Blood samples were obtained from her during the relapse in August 2002 (while the patient was receiving 15 mg/day prednisolone) and 3 months after the remission of this episode of relapse (while the patient was receiving 15 mg/day prednisolone therapy).

In this study, we also examined blood samples from 29 patients during the nephrosis and remission phases with biopsy-proven MCNS, 30 healthy subjects and 57 patients with nephrotic syndrome [biopsy-proven; 27 with FSGS and 30 with membranous nephropathy (MN)]. The protocol of this study was approved by the ethics committee of the institution involved and informed consent for genetic studies was obtained from all subjects.

SAGE protocol
The libraries for SAGE of PBMC from Patient 1 during nephrosis and remission phases were generated as described previously [10]. Total RNA was prepared using a Trizol reagent (Gibco-BRL, Gaithersburg, MD, USA). PolyA+ RNA was obtained using a Messagemaker kit (Gibco-BRL) according to the manufacturer's instruction and was converted to cDNA with a SuperScript Choice System (Gibco-BRL) with a 5'-biotinylated oligo(dT). Biotinylated double-strand cDNA was cleaved with the restriction enzyme NlaIII (New England Biolaboratories, Beverly, MA, USA) and the 3'-terminal fragments were bound to streptoavidin-coated magnetic beads (Dynal, Oslo, Norway). Captured 3' cDNA fragments were divided into two pools and each pool was ligated to one of the linkers containing recognition sites for BsmFI.

Nucleotide sequences of the linkers were as follows:

Linker 1
5'-TTTGGATTTGCTGGTGCAGTACAACT AGGCTTAATAGGGACATG-3'

5'-TCCCTATTAAGCCTAGTTGTACTGCA CCAGCAAATCC[amino modifier C5]-3'

Linker 2
5'-TTTCTGCTCGAATTCAAGCTTCTAAC GATGTACGGGGACATG-3'

5'-TCCCCGTACATCGTTAGAAGCTTGAA TTCGAGCAG[amino modifier C5]-3'

Linkered cDNAs were released from the beads by digestion with BsmFI. After digestion, the linker tags were blunted with Klenow fragments and were ligated to each other to generate ‘ditags’ (tags ligated tail-to-tail). The ditags were amplified with polymerase chain reaction (PCR) in 32 cycles, with 5'-GGATTTGCTGGTGCAGTACA-3' and 5'-CTGCT CGAATTCAAGCTTCT-3' as primers.

PCR products were analysed by polyacrylamide gel electrophoresis (PAGE) and the band containing the ditags was excised. After digestion with NlaIII, the ditags were ligated together to produce concatemers. The concatemers were separated by PAGE, and the products that consisted of between 400 and 1200 base pairs (bp) were excised. These products were cloned into pZero-1 (Invitrogen, Carlsbad, CA, USA), digested with SphI (New England Biolaboratories). PCR for insert screening of colonies was performed with the M13 forward and reverse sequences as primers. PCR products longer than 600 bp were sequenced using the BigDye terminator cycle sequence kit (Perkin-Elmer Applied Biosystems, Foster City, CA, USA). Sequencing was performed with an ABI 377 automated DNA sequencer (Perkin-Elmer Applied Biosystems).

SAGE data analysis
Concatemer sequences were analysed as described previously [10] with the SAGE 2000 software, version 4.12, which was kindly provided by Dr Kinzler (Johns Hopkins University). To identify the individual genes, the search for the expressed genes was conducted at the Serial Analysis of Gene Expression Tag of the Gene Mapping home page (http://www.ncbi.nlm.gov/SAGE). The detailed SAGE protocol can be seen at the SAGE home page (http://www.sagenet.org).

Quantitative real-time RT–PCR
We quantified TRAIL and TIMP-1 mRNA expressions in the nephrosis and remission PBMC samples from four MCNS patients (including Patient 1) and eight MN patients. Table 1 summarizes the medical regimens of these patients at the time blood samples were obtained.


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  		Table 1. Profiles and data of patients with MCNS and MN examined by real-time RT-PCR

 
Total RNA was prepared with an RNeasy kit (Qiagen, Hilden, Germany) and used for cDNA synthesis with an oligo(dT) primer (Amersham Biosciences, Piscataway, NJ, USA), as described previously [10]. The following PCR primers were used:
TRAIL-specific forward primer
5'-ATGGCTATGATGG AGGTCCAG-3'

TRAIL-specific reverse primer
5'-TTGTCCTGCATCT GCTTCAGC-3'

TIMP-1-specific forward primer
5'-CTGTTGTTGCTG TGGCTGATA-3'

TIMP-1-specific reverse primer
5'-CCGTCCACAAGCA ATGAGT-3'

ß-actin-specific forward primer
5'-CAAGAGATGGCC ACGGCTGCT-3'

ß-actin-specific reverse primer
5'-TCCTTCTGCATCC TGTCGGCA-3'

We confirmed that each PCR product had a single band on agarose gel electrophoresis and that each of the sequence data were correct.

Real-time reverse transcription (RT)–PCR reaction was carried out according to the manufacturer's instructions in a final 20 µl volume containing 10 µl DNA Master Hybridization Probe 2X (Qiagen), 1 µl of 10 pmol forward and reverse primers, 1 µl cDNA and 7 µl water. After an initial denaturation step at 95°C for 900 s, temperature cycling was initiated. Each cycle consisted of denaturation at 95°C for 15 s, hybridization at 56°C (for TRAIL and ß-actin) or at 60°C (for TIMP-1) for 20 s and elongation at 72°C for 20 s, using a LightCycler (Roche Diagnostics, Mannheim, Germany). Forty-five cycles were performed and each sample was run in triplicate.

Quantitative real-time RT–PCR curves were analysed by the LightCycler 3.5 software (Roche Diagnostics). For the relative quantification of TRAIL and TIMP-1 mRNA expressions, the mRNA expression of ß-actin was used as a control.

ELISA for a soluble form of TRAIL
Serum levels of a soluble form of TRAIL (sTRAIL) were measured in duplicate for each sample, using an enzyme-linked immunosorbent assay (ELISA) kit for sTRAIL (Active Motif North America, Carlsbad, CA, USA). Optical density was measured in an ELISA reader at 405 nm. Concentrations of sTRAIL were determined by a standard curve, according to the manufacturer's instructions.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Generation and analysis of SAGE tags from PBMC from an MCNS patient during nephrosis and remission phases
SAGE libraries were constructed from PBMC obtained from Patient 1 during nephrosis and remission phases. We obtained 10 606 tags from a nephrosis sample and 10 171 tags from a remission sample. Using these SAGE tags, we searched for up- and down-regulated genes in the nephrosis PBMC sample. Tables 2 and 3 list the tags differentially expressed in the nephrosis PBMC sample at levels >4-fold higher or lower, respectively, than in the remission sample. In Tables 2 and 3, we have listed GenBank matches of tags derived from functionally known genes, except for genes for ribosomal proteins.


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  		Table 2. Up-regulated PBMC gene transcripts from Patient 1 with MCNS in the nephrosis phase

 

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  		Table 3. Down-regulated PBMC gene transcripts from Patient 1 with MCNS in the nephrosis phase

 
Among up-regulated genes in the nephrosis PBMC sample (Table 2), there were genes for secretory proteins (TRAIL and TIMP-1) and genes for proteins involved in signalling pathways (calcium/calmodulin-dependent protein kinase kinase 1, mitogen-activated protein kinase-activated protein kinase 2, FK506 binding protein 1A and cyclophilin F). On the other hand, down-regulated genes in the nephrosis PMBC sample mainly encoded membrane-associated proteins (Table 3).

Quantification of TRAIL and TIMP-1 mRNA expressions in PBMC from MCNS patients during nephrosis and remission phases by real-time RT–PCR
SAGE showed that two genes for secretory proteins (TRAIL and TIMP-1) were up-regulated in the PBMC from Patient 1 during the nephrosis phase of MCNS (Table 2). To confirm this result, we performed quantitative real-time RT–PCR analyses for TRAIL and TIMP-1 mRNA expressions in nephrosis and remission PBMC samples from seven additional MCNS patients. We confirmed that TRAIL mRNA expressions were higher in the nephrosis samples than in the remission samples from all the MCNS patients analysed (patients 1–8 in Table 1). On the other hand, we could not confirm that the expressions of TIMP-1 mRNA in the nephrosis PBMC samples were higher than in the remission samples from all the MCNS patients (Table 1).

We also examined TRAIL mRNA expressions in the nephrosis and remission PBMC samples from four MN patients. The results showed that expression patterns were variable among these patients (patients 9–12 in Table 1).

Serum sTRAIL levels in MCNS patients during nephrosis and remission phases
Based on the results of SAGE and real-time RT–PCR analyses, we used ELISA to measure serum sTRAIL levels in 29 MCNS patients during the nephrosis and remission phases. We also measured serum sTRAIL levels in 30 healthy subjects and 57 patients with nephrotic syndrome due to other types of glomerular diseases (27 FSGS and 30 MN). The results showed that there was no significant increase in the serum sTRAIL level in MCNS patients during the nephrosis phase (Figure 1).



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  		Fig. 1. ELISA for serum sTRAIL levels in patients with nephrotic syndrome and healthy individuals. We examined sera from 30 healthy individuals (Cont), 29 MCNS patients during both the nephrotic and remission phases (MCNS-N and MCNS-R), 27 patients with FSGS and 30 patients with MN. The bars indicate the median value for each group.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In this study, we prepared for SAGE PBMC samples obtained from an MCNS patient during nephrosis and remission phases, and identified various up- and down-regulated genes in PBMC during the nephrosis phase. Since the MCNS samples were obtained while this patient received the same dosage of steroids during the two phases, the influence of steroids on the results of SAGE in this one patient can be excluded. For further studies, we selected two up-regulated genes encoding TRAIL and TIMP-1, which can be secreted by PBMC into the blood. Quantitative real-time RT–PCR analysis confirmed an increased TRAIL mRNA expression in nephrosis PBMC samples from all the MCNS patients examined. On the other hand, the TRAIL mRNA expression pattern was variable among nephrotic patients with MN. This suggests that the high TRAIL mRNA expression in the nephrosis PBMC samples from MCNS patients could not represent a condition associated with a nephrotic state. ELISA showed that there was no significant increase of serum sTRAIL levels in MCNS patients during the nephrosis phase.

Sahali et al. [6] recently reported their findings of a subtracted cDNA library screening, using cDNA from PBMC from the same MCNS patient and comparing the relapse and remission phases. They found various up-regulated PBMC transcripts for signalling pathways, including the mitogen-activated protein kinase cascade. Our SAGE results also showed considerable differences in the expression profiles between nephrosis and relapse PBMC samples from the same MCNS patient. During the nephrosis phase, there were several up-regulated genes for various proteins involved in signalling pathways, such as calcium/calmodulin-dependent protein kinase kinase 1, mitogen-activated protein kinase-activated protein kinase, FK506 binding protein 1A and cyclophilin F, in addition to the gene for TRAIL. These observations suggest that multiple signalling pathways might be activated in PBMC during the development of MCNS.

TRAIL (also known as Apo-2 ligand) has been identified as a member of the TNF ligand family that induces apoptosis in a wide variety of tumour cells [8,9]. TRAIL can selectively induce apoptosis in tumorigenic cells, but not in normal cells, highlighting its potential therapeutic application in cancer treatment. In contrast to other members of the TNF ligand family, which are often only transiently expressed on activated cells, TRAIL mRNA is expressed constitutively in a wide range of tissues [8]. Although TRAIL is primarily expressed as a type II transmembrane protein, bioactive sTRAIL might be released from activated T-cells in association with microvesicles or cleaved from the cell surface by proteases, or both [11,12]. Thus, the serum levels of sTRAIL are likely to be regulated not only by mRNA TRAIL expressions in PBMC but also by other factors. This might be the reason why in our study there was no correlation between the levels of mRNA TRAIL expression in PBMC and serum sTRAIL in MCNS patients during nephrosis.

Several studies have demonstrated that TRAIL is associated with the pathogenesis of some autoimmune diseases, such as neutropenia of systemic lupus erythematosus [13 and references therein]. However, there have been no reports suggesting the possibility of TRAIL being associated with the pathogenesis of MCNS. Our results suggest that the intracellular TRAIL mRNA expression is up-regulated in PBMC during the nephrosis phase of MCNS, although the bulk of the investigations were based on preliminary SAGE findings from a single patient and real-time RT–PCR findings from a total of eight patients. Our observations could represent an epiphenomenon or they could provide a potential explanation for the altered T-cell function seen in MCNS.

It is known that therapeutic concentrations of IFN-ß and IFN-{alpha} stimulate the expression of high levels of TRAIL mRNA in PBMC and neutrophils, and the release of elevated amounts of sTRAIL [14,15]. In fact, there are several case reports that describe an acute onset or a relapse of MCNS during the therapy of malignancies, or chronic viral hepatitis with IFN-ß or IFN-{alpha} [16–19]. It is therefore possible that the up-regulation of a TRAIL induced by IFN-ß or IFN-{alpha} might be involved in the development of MCNS in these cases. In particular, nephrotic-range proteinuria regressed without steroid treatment after the cessation of IFN-ß injections in the case reported by Nakao et al. [17]. Although TRAIL is now considered to have a promising therapeutic potential in cancer treatment [20], careful patient monitoring, including urinalysis, will be necessary when using it.



   Acknowledgments
 
This work was supported, in part, by the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 28. 7.04
Accepted in revised form: 19.11.04


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Proteomic analysis of mononuclear cells of patients with minimal-change nephrotic syndrome of childhood
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