Expression of miR-142-5p in Peripheral Blood Mononuclear Cells from Renal Transplant Patients with Chronic Antibody-Mediated Rejection

Richard Danger,Yohann Foucher,Annaïck Pallier,Jean-Paul Duong Van Huyen,Maxim Durand,Magali Giral,Sophie Brouard,Jean-Paul Soulillou,Amélie Lavault,Chloé Paul,Michel Delahousse,Karine Renaudin,Nicolas Degauque,Stéphanie Castagnet

doi:10.1371/journal.pone.0060702

Abstract

In renal transplantation, the unresponsiveness of patients undergoing chronic antibody mediated rejection (CAMR) to classical treatment stress on the need for accurate biomarkers to improve its diagnosis. We aim to determine whether microRNA expression patterns may be associated with a diagnosis of CAMR. We performed expression profiling of miRNAs in peripheral blood mononuclear cells (PBMC) of kidney transplant recipients with CAMR or stable graft function. Among 257 expressed miRNAs, 10 miRNAs associated with CAMR were selected. Among them, miR-142-5p was increased in PBMC and biopsies of patients with CAMR as well as in a rodent model of CAMR. The lack of modulation of miR-142-5p in PBMC of patients with renal failure, suggests that its over-expression in CAMR was associated with immunological disorders rather than renal dysfunction. A ROC curve analysis performed on independent samples showed that miR-142-5p is a potential biomarker of CAMR allowing a very good discrimination of the patients with CAMR (AUC = 0.74; p = 0.0056). Moreover, its expression was decreased in PHA-activated blood cells and was not modulated in PBMC from patients with acute rejection, excluding a non-specific T cell activation expression. The absence of modulation of this miRNA in immunosuppressed patients suggests that its expression was not influenced by treatment. Finally, the analysis of miR-142-5p predicted targets under-expressed in CAMR PBMC in a published microarray dataset revealed an enrichment of immune-related genes. Altogether, these data suggest that miR-142-5p could be used as a biomarker in CAMR and these finding may improve our understanding of chronic rejection mechanisms.

Highlights

Chronic antibody-mediated rejection (CAMR) is a major cause of kidney graft loss after one year [1]
381 miRNAs was measured in peripheral blood mononuclear cells (PBMC) from 9 CAMR and 10 stable graft function (STA) patients. 257 miRNAs were expressed with a cycle of quantification (Cq) below 35 in at least half of the samples in each group
We measured the expression of four miRNAs from the signature: miR-301a, miR-125b, miR-503 and miR-590-5p (Figure S1). miR-590-5p was significantly up-regulated in blood from patients with CAMR according Taqman low density arrays (TLDA) and PCR (p = 0.049). miR-125b and miR-503 displays down- and up-regulation, respectively, without reaching significance (p-value.0.05) whereas no difference was observed for miR-301a

Summary

Introduction

Chronic antibody-mediated rejection (CAMR) is a major cause of kidney graft loss after one year [1]. The process leading to this phenomenon is not yet fully understood [2,3] whereas the diagnosis of CAMR is established by histological analysis and detection of circulating Donor Specifc Antibodies (DSA) [4], predicting its future occurrence remains elusive and functional parameters such as creatinemia and proteinuria, currently used in clinical practice, cannot detect CAMR early enough to prevent irreversible graft alterations. There is currently growing interest in microRNAs (miRNAs), which can repress the expression of numerous genes and thereby influence large downstream networks [6]. These small molecules are involved in various biological mechanisms and diseases as well as in the regulation of immune mechanisms. Whereas the high stability of miRNAs favors them as potential biomarkers [13], their detection and potential role in CAMR have not yet been explored

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