Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis

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Abstract

Background

Primary membranous nephropathy (PMN) is an important cause of nephrotic syndrome in adults. Urine proteome may provide important clues of pathophysiological mechanisms in PMN. In the current study, we analyzed and compared the proteome of urine from patients with PMN and normal controls.

Methods

We performed two technical replicates (TMT1 and TMT2) to analyze and compare the urine proteome from patients with PMN and normal controls by tandem mass tag (TMT) technology coupled with nanoscale liquid chromatography tandem mass spectrometry analysis (LC–MS/MS). Gene ontology (GO) enrichment analysis was performed to analyse general characterization of the proteins. The proteins were also matched against the database of Kyoto Encyclopedia of Genes and Genomes (KEGG). For validation, Western blot was used to analyze the selected proteins.

Results

A total of 509 proteins and 411 proteins were identified in TMT1 and TMT2, respectively. 249 proteins were both identified in two technical replicates. GO analysis and KEGG analysis revealed immunization and coagulation were predominantly involved. Among the differential protein, the overexcretion of alpha-1-antitrypsin (A1AT) and afamin (AFM) were validated by Western blot analysis.

Conclusions

Our data showed the important role of immunologic mechanism in the development of PMN, and the value of urinary A1AT and AFM in biomarker discovery of patients with PMN. The discovery of the overexcretion of A1AT and AFM in the urine can help to further elucidate pathogenetic mechanisms involved in PMN.

Electronic supplementary material

The online version of this article (10.1186/s12014-018-9183-3) contains supplementary material, which is available to authorized users.

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Most cited references 36

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Gene Ontology: tool for the unification of biology

Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)

Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.

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Primary Membranous Nephropathy.

William G. Couser (2017)

Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.

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The incidence of primary glomerulonephritis worldwide: a systematic review of the literature.

A. McGrogan, C. F. M. Franssen, C. S. de Vries (2011)

Little is known about the worldwide variation in incidence of primary glomerulonephritis (GN). The objective of this review was to critically appraise studies of incidence published in 1980-2010 so that an overall view of trends of these diseases can be found. This would provide important information for determining changes in rates and understanding variations between countries. All relevant papers found through searches of Medline, Embase and ScienceDirect were critically appraised and an assessment was made of the reliability of the reported incidence data. This review includes 40 studies of incidence of primary GN from Europe, North and South America, Canada, Australasia and the Middle East. Rates for the individual types of disease were found to be in adults, 0.2/100,000/year for membrano-proliferative GN, 0.2/100,000/year for mesangio-proliferative GN, 0.6/100,000/year for minimal change disease, 0.8/100,000/year for focal segmental glomerulosclerosis, 1.2/100,000/year for membranous nephropathy and 2.5/100,000/year for IgA nephropathy. Rates were lower in children at around 0.1/100,000/year with the exception of minimal change disease where incidence was reported to be 2.0/100,000/year in Caucasian children with higher rates in Arabian children (9.2/100,000/year) and Asian children (6.2-15.6/100,000/year). This study found that incidence rates of primary GN vary between 0.2/100,000/year and 2.5/100,000/year. The incidence of IgA nephropathy is at least 2.5/100,000/year in adults; this disease can exist subclinically and is therefore only detected by chance in some patients. In addition, referral policies for diagnostic biopsy vary between countries. This will affect the incidence rates found.

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Author and article information

Contributors

Lu Pang: panglu@hsc.pku.edu.cn

Qianqian Li: liqianqian.2006@163.com

Yan Li: yanli001@gmail.com

Yi Liu: liuyiflyhigh@126.com

Nan Duan: studentduan@163.com

Haixia Li: haixiali@hsc.pku.edu.cn

Journal

Journal ID (nlm-ta): Clin Proteomics

Journal ID (iso-abbrev): Clin Proteomics

Title: Clinical Proteomics

Publisher: BioMed Central (London )

ISSN (Print): 1542-6416

ISSN (Electronic): 1559-0275

Publication date (Electronic): 7 February 2018

Publication date PMC-release: 7 February 2018

Publication date Collection: 2018

Volume: 15

Electronic Location Identifier: 5

Affiliations

[1 ]ISNI 0000 0004 1764 1621, GRID grid.411472.5, Department of Clinical Laboratory, , Peking University First Hospital, ; Beijing, China

[2 ]ISNI 0000000119573309, GRID grid.9227.e, Laboratory of Interdisciplinary Research, Institute of Biophysics, , Chinese Academy of Sciences, ; Beijing, China

Article

Publisher ID: 9183

DOI: 10.1186/s12014-018-9183-3

PMC ID: 5801694

PubMed ID: 29445323

SO-VID: c0e0395e-8a15-458f-b0ed-e1aaa3fb75a5

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 2 September 2017

Date accepted : 30 January 2018

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: primary membranous nephropathy,urine,proteomics,alpha-1-antitrypsin,afamin

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ScienceOpen disciplines: Molecular medicine

Keywords: primary membranous nephropathy, urine, proteomics, alpha-1-antitrypsin, afamin

Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis

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Conclusions

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Genome Engineering using CRISPR

Most cited references 36

Gene Ontology: tool for the unification of biology

Primary Membranous Nephropathy.

The incidence of primary glomerulonephritis worldwide: a systematic review of the literature.

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