The endogenous repair process can result in recovery after acute kidney injury (AKI) with adaptive proliferation of tubular epithelial cells, but repair can also lead to fibrosis and progressive ...kidney disease. There is currently limited knowledge about transcriptional regulators regulating these repair programs. Herein we establish the enhancer and super-enhancer landscape after AKI by ChIP-seq in uninjured and repairing kidneys on day two after ischemia reperfusion injury (IRI). We identify key transcription factors including HNF4A, GR, STAT3 and STAT5, which show specific binding at enhancer and super-enhancer sites, revealing enhancer dynamics and transcriptional changes during kidney repair. Loss of bromodomain-containing protein 4 function before IRI leads to impaired recovery after AKI and increased mortality. Our comprehensive analysis of epigenetic changes after kidney injury in vivo has the potential to identify targets for therapeutic intervention. Importantly, our data also call attention to potential caveats involved in use of BET inhibitors in patients at risk for AKI.
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).
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.
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-β 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.
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.
ABSTRACT
Background Biocompatibility of haemodialysis membranes is the most important quality criteria to enable long‐term dialysis without major harmful effects. This study sought to evaluate the ...differences of genomic signatures derived from peripheral blood mononuclear cells (PBMC) in patients undergoing haemodialysis treatment using two different dialyser membranes: one semi‐synthetic and one full‐synthetic membrane.
Design Microarray experiments were conducted in PBMCs of four stable haemodialysis patients before and after dialysis comparing semi‐synthetic (Hemophan® GFS Plus 16) and full‐synthetic (Hemoflow® FX80) dialysis membranes, respectively. Genes differentially expressed when comparing the two different membranes used were analysed in order to elucidate the underlying molecular mechanisms affecting PBMCs in the course of dialysis treatment.
Results One hundred and seventy‐two genes were identified as up‐regulated after treatment with semi‐synthetic membranes when compared to full‐synthetic membranes. These genes could be assigned to processes including immunity and defence, signal transduction, and apoptosis. Dialysis with a full‐synthetic membrane, on the other hand, led to an activation of 72 genes that were mainly involved in cell cycle and cell cycle control.
Conclusion The over‐representation of genes belonging to immunity/defence, signal transduction, and apoptosis as found with semi‐synthetic membranes suggests that full‐synthetic membranes are more biocompatible than semi‐synthetic membranes.
The discovery of novel classes of non-coding RNAs (ncRNAs) has revolutionized medicine. Long thought to be a mere cellular housekeeper, surprising functions have recently been uncovered. MicroRNAs ...(miRNAs), are a representative of the class of short ncRNAs, play a fundamental role in the control of DNA and protein biosynthesis and activity as well as pathology. Currently, miRNAs are being investigated as diagnostic and prognostic markers and potential therapeutic targets in kidney transplantation for such indolent processes as ischaemia-reperfusion injury, humoral rejection or viral infections. It is realistic to believe that monitoring of renal allograft recipients in the future will include genome-wide miRNA profiling of biological fluids. Based on these individual profiles, an informed decision on therapeutic consequences will be possible. A first success with a specific suppression of miRNAs by antisense oligonucleotides was achieved in experimental studies of reperfusion injury and humoral rejection. Proof of this concept in men comes from studies in such indolent viral infections as Ebola and hepatitis C, where anti-miR therapy led to sustained viral clearance. In this review, we summarize the basis of the recent ncRNA revolution and its implication for kidney transplantation.
Several studies investigated the association of histologic scores of donor kidney biopsies obtained before engraftment with posttransplant outcomes. Discrimination and goodness of fit of these ...scores, however, is low.
Thus, we sought to identify and elucidate the performance of molecular rather than histologic markers for this purpose using whole genome gene expression microarray experiments.
We identified 80 unique differentially regulated genes in 82 samples, showing no histologic damage versus those with histologic damage, based on the Chronic Allograft Damage Index (CADI) and acute tubular injury. Main biological categories enriched with up-regulated genes in damaged tissue were "immunity and defense," "cell communication," or "apoptosis." Interestingly, genes involved in cell structure, cell adhesion, and protein trafficking were specific for tubular atrophy. Histology (CADI score) explained only 14% of the variability of 1 year creatinine (adjusted R2 for panel-reactive antibodies, biopsy confirmed acute rejection, and sum of human leukocyte antigen mismatches) whereas a combination of three biomarkers without clinical covariables explained 28%. The three molecular markers are the NLR family, pyrin domain containing 2 (NLRP2), immunoglobulin J polypeptide, and the regulator of G-protein signaling 5.
In summary, we identified biomarkers in transplant kidney biopsies, which are predictive for medium-term allograft function.
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