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Clinical ResearchGlomerulonephritis and Interstitial Nephritis
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Molecular Characterization of Membranous Nephropathy

Rachel Sealfon, Laura Mariani, Carmen Avila-Casado, Viji Nair, Rajasree Menon, Julien Funk, Aaron Wong, Gabriel Lerner, Norifumi Hayashi, Olga Troyanskaya, Matthias Kretzler and Laurence H. Beck
JASN June 2022, 33 (6) 1208-1221; DOI: https://doi.org/10.1681/ASN.2021060784
Rachel Sealfon
1Center for Computational Biology, Flatiron Institute, New York, New York
2Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey
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Laura Mariani
3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Carmen Avila-Casado
4Toronto General Hospital Research Institute, Toronto, Ontario, Canada
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Viji Nair
3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Rajasree Menon
3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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Julien Funk
1Center for Computational Biology, Flatiron Institute, New York, New York
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Aaron Wong
1Center for Computational Biology, Flatiron Institute, New York, New York
2Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey
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Gabriel Lerner
5Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
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Norifumi Hayashi
5Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
6Division of Nephrology, Kanazawa Medical University, Uchinada, Ishikawa, Japan
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Olga Troyanskaya
1Center for Computational Biology, Flatiron Institute, New York, New York
2Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey
7Department of Computer Science, Princeton University, Princeton, New Jersey
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Matthias Kretzler
3Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
8Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
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Laurence H. Beck Jr.
5Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts
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Significance Statement

Although membranous nephropathy (MN) is one of the most common causes of nephrotic syndrome, the molecular characteristics of the kidney damage in MN remain poorly defined. In this study, the authors applied a machine-learning framework to predict diagnosis on the basis of gene expression in microdissected kidney tissue from patients with glomerulonephropathies. They found that MN has a glomerular transcriptional signature that distinguishes it from other glomerulonephropathies and identified a set of MN-specific genes differentially expressed across two independent cohorts and robustly recovered in an additional validation cohort. They also found the MN-specific genes are enriched in targets of transcription factor NF-κB and are predominantly expressed in podocytes. This work provides a molecular snapshot of MN and elucidates transcriptional alterations specific to this disease.

Abstract

Background Molecular characterization of nephropathies may facilitate pathophysiologic insight, development of targeted therapeutics, and transcriptome-based disease classification. Although membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome, the molecular pathways of kidney damage in MN require further definition.

Methods We applied a machine-learning framework to predict diagnosis on the basis of gene expression from the microdissected kidney tissue of participants in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We sought to identify differentially expressed genes between participants with MN versus those of other glomerulonephropathies across the NEPTUNE and European Renal cDNA Bank (ERCB) cohorts, to find MN-specific gene modules in a kidney-specific functional network, and to identify cell-type specificity of MN-specific genes using single-cell sequencing data from reference nephrectomy tissue.

Results Glomerular gene expression alone accurately separated participants with MN from those with other nephrotic syndrome etiologies. The top predictive classifier genes from NEPTUNE participants were also differentially expressed in the ERCB participants with MN. We identified a signature of 158 genes that are significantly differentially expressed in MN across both cohorts, finding 120 of these in a validation cohort. This signature is enriched in targets of transcription factor NF-κB. Clustering these MN-specific genes in a kidney-specific functional network uncovered modules with functional enrichments, including in ion transport, cell projection morphogenesis, regulation of adhesion, and wounding response. Expression data from reference nephrectomy tissue indicated 43% of these genes are most highly expressed by podocytes.

Conclusions These results suggest that, relative to other glomerulonephropathies, MN has a distinctive molecular signature that includes upregulation of many podocyte-expressed genes, provides a molecular snapshot of MN, and facilitates insight into MN’s underlying pathophysiology.

  • membranous nephropathy
  • transcriptional profiling
  • podocyte
  • single-cell sequencing
  • machine learning
  • scRNA-seq
  • machine learning
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (6)
Journal of the American Society of Nephrology
Vol. 33, Issue 6
June 2022
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Molecular Characterization of Membranous Nephropathy
Rachel Sealfon, Laura Mariani, Carmen Avila-Casado, Viji Nair, Rajasree Menon, Julien Funk, Aaron Wong, Gabriel Lerner, Norifumi Hayashi, Olga Troyanskaya, Matthias Kretzler, Laurence H. Beck
JASN Jun 2022, 33 (6) 1208-1221; DOI: 10.1681/ASN.2021060784

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Molecular Characterization of Membranous Nephropathy
Rachel Sealfon, Laura Mariani, Carmen Avila-Casado, Viji Nair, Rajasree Menon, Julien Funk, Aaron Wong, Gabriel Lerner, Norifumi Hayashi, Olga Troyanskaya, Matthias Kretzler, Laurence H. Beck
JASN Jun 2022, 33 (6) 1208-1221; DOI: 10.1681/ASN.2021060784
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Keywords

  • membranous nephropathy
  • transcriptional profiling
  • podocyte
  • single-cell sequencing
  • machine learning
  • scRNA-seq

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