miRNA Profiling Discriminates Types of Rejection and Injury in Human Renal Allografts

Background. Increasing evidence accumulates on the central involvement of microRNAs (miRNAs) in disease pathophysiology. We identified distinctly deregulated miRNAs in human renal allograft biopsies from patients undergoing acute cellular rejection, antibody-mediated rejection (ABMR), and delayed graft function (DGF). Methods. Sixty-five posttransplantation kidney biopsy samples covering 41 cases with acute rejection (15 vascular rejection, 15 interstitial rejection, and 11 ABMR), 14 DGF cases, and 10 protocol biopsies serving as controls were analyzed using the Affymetrix GeneChip miRNA Array. Differentially regulated miRNAs were identified by Student's t test and Bonferroni correction. Target genes for the set of miRNAs were retrieved from miRTarBase (experimentally verified targets) as well as by applying the target prediction routines DIANAmT, miRanda, and Targetscan. Results. Patients with acute cellular rejection, ABMR, and DGF discriminate from the control group (protocol biopsies) in unsupervised clustering of miRNA profiles, clearly identifying deregulated miRNAs in rejection and DGF. Angiogenesis, apoptosis, and transforming growth factor-A signaling were identified as relevant pathways in ischemic response following an integrative analysis of miRNA targets and mRNA expression profiles. Inflammation by chemokine and cytokine signaling, T-cell activation, and B-cell activation were identified as relevant in acute rejection accordingly. Conclusion. These data suggest that distinct miRNA signatures playing a role in specific biological pathways discriminate acute cellular and humoral rejection and DGF. This finding serves as valuable tool for a rational selection of diagnostic, prognostic, and potentially therapeutic molecular targets of posttransplantation events.