miRNA regulation of renal transplant rejection and acute transplant failure

Kidney transplantation is the preferred treatment option for patients with end-stage renal disease. Average graft survival nowadays is about 14 years due to advanced medical treatments and immunosuppressive therapies. Nonetheless two events severely reduce graft survival time, namely acute renal transplant failure (ARTF) and early rejection episodes. ARTF occurs in roughly 25% of cases and 20% of transplant recipients experience early rejection episodes. Various molecular mechanisms have been elucidated in recent years in these two clinical settings leading to the design of more specific and effective immunosuppressive and therapeutic medication. A complete prevention of ARTF and acute rejection after transplantation is desirable but still not feasible. MicroRNAs (miRNAs), are a class of small non-coding 18 to 24 nucleotide-long RNAs that have been implicated recently in diverse cellular functions, could be the missing jigsaw piece in this puzzle and provide further insight into the mechanisms of ARTF and acute rejection episodes. The involvement of miRNAs has not been studied in renal allografts so far and could have major impact on the differential diagnosis or the choice of patient treatment following renal transplantation. The project of the proposal at hand has two specific aims: The first specific aim of the project is the identification of miRNAs in renal biopsies from patients who develop acute renal transplant failure immediately after engraftment. In addition target genes of these deregulated miRNAs will be identified and analyzed on a functional level. The identified miRNAs and target genes will provide novel insights in the molecular regulation of acute renal failure potentially paving the way for novel therapeutic interventions. Additionally the identified molecules may serve as novel diagnostic markers. The second specific aim of the project is the identification of miRNAs and their target genes associated with acute rejection in renal transplantation. In particular we will evaluate whether the molecular regulation of acute interstitial rejection is different from acute vascular rejection thus providing novel insight into the differential diagnosis of acute renal allograft rejection.

Kidney transplantation is the preferred treatment of end stage renal disease, because compared to dialysis it expands life expectancy and enhances quality of life. The main complications after renal transplantation are acute renal allograft failure (ARF) and acute rejection. Although advancing immunosuppression protocols have continuously improved short time graft survival by avoidance of acute rejection episodes, the rate of ARF remained at roughly 25% in deceased donor transplantation over the last decades. ARF is the strongest predictor of premature renal allograft failure. Over the last years great efforts have been undertaken to reveal the underlying molecular mechanism, mainly on the mRNA level, of acute renal failure. But so far no integrated biology approach was used to uncover the co-regulation and choreography of molecular pathways in this setting, which is probably the reason that prevention of ARF is still an unsolved medical need in renal transplantation.Therefore, we investigated in this FWF-project the hierarchical molecular regulation and choreography also on the post-transcriptional level by using omics-wide microRNA analyses (miRNAs). miRNAs are a class of small non-coding 18 to 24 nucleotide-long RNAs that have been implicated recently as powerful regulators of diverse cellular processes including roles in disease and tissue remodeling. miRNAs regulate their target genes either by degradation or by inhibition of the translation into protein. We identified for the first time specific miRNA signatures such as miRNA182, which discriminate ARF and acute cellular and antibody-mediated rejection from well-functioning human allografts. A new integrative Systems Biology approach was used to interlink miRNA profiles, mRNA profiles and in-silico target prediction for the validation and biological interpretation of the results. Our findings serve as basis for the selection of diagnostic, prognostic and potentially therapeutic molecular targets of post-transplant events. A follow-up project for the evaluation of specific miRNA inhibitors as therapeutic tool for the prevention of acute renal failure has been already funded by the FWF (P25726) and was the foundation of a successful EU-Marie Curie IOF application by the projects postdoc Dr. Julia Wilflingseder (MC#328613).