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Transplantation. 2016 Oct;100(10):2062-70. doi: 10.1097/TP.0000000000001214.

Intragraft Antiviral-Specific Gene Expression as a Distinctive Transcriptional Signature for Studies in Polyomavirus-Associated Nephropathy.

Author information

1
1 Department of Surgery, University of California, San Francisco, San Francisco, CA. 2 Kidney Transplant Unit, Bellvitge University Hospital, IDIBELL, UB, Barcelona, Spain. 3 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 4 Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.

Abstract

BACKGROUND:

Polyomavirus nephropathy (PVAN) is a common cause of kidney allograft dysfunction and loss. To identify PVAN-specific gene expression and underlying molecular mechanisms, we analyzed kidney biopsies with and without PVAN.

METHODS:

The study included 168 posttransplant renal allograft biopsies (T cell-mediated rejection [TCMR] = 26, PVAN = 10, normal functioning graft = 73, and interstitial fibrosis/tubular atrophy = 59) from 168 unique kidney allograft recipients. We performed gene expression assays and bioinformatics analysis to identify a set of PVAN-specific genes. Validity and relevance of a subset of these genes are validated by quantitative polymerase chain reaction and immunohistochemistry.

RESULTS:

Unsupervised hierarchical clustering analysis of all the biopsies revealed high similarity between PVAN and TCMR gene expression. Increased statistical stringency identified 158 and 252 unique PVAN and TCMR injury-specific gene transcripts respectively. Although TCMR-specific genes were overwhelmingly involved in immune response costimulation and TCR signaling, PVAN-specific genes were mainly related to DNA replication process, RNA polymerase assembly, and pathogen recognition receptors. A principal component analysis (PCA) using these genes further confirmed the most optimal separation between the 3 different clinical phenotypes. Validation of 4 PVAN-specific genes (RPS15, complement factor D, lactotransferrin, and nitric oxide synthase interacting protein) by quantitative polymerase chain reaction and confirmation by immunohistochemistry of 2 PVAN-specific proteins with antiviral function (lactotransferrin and IFN-inducible transmembrane 1) was done.

CONCLUSIONS:

In conclusion, even though PVAN and TCMR kidney allografts share great similarities on gene perturbation, PVAN-specific genes were identified with well-known antiviral properties that provide tools for discerning PVAN and AR as well as attractive targets for rational drug design.

PMID:
27140517
PMCID:
PMC5235336
DOI:
10.1097/TP.0000000000001214
[Indexed for MEDLINE]
Free PMC Article

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