MIR182_KIDNEY-TX · miR-182 as new Therapeutical Target in Renal Transplantation

miR-182 as new Therapeutical Target in Renal Transplantation

Acute kidney injury (AKI) remains a major clinical event associated with unacceptably high mortality rates, progression to end-stage renal disease, and rising incidence, severity, and cost. Ischemia and subsequent reperfusion injury (IRI) is one of the major causes of AKI. Especially in transplantation, where it is an unavoidable phenomenon, IRI contributes besides other main risk factors such as advanced donor age to high rates of post-transplant AKI also known as delayed graft function associated with reduced long-term graft survival and transition to chronic allograft dysfunction. Certainly kidneys have an intrinsic ability to repair after significant injury. However, this process is inefficient and fails to some extend in these kidneys. Strategies to promote endogenous repair processes and minimize associated injury, fibrosis and necrosis are ultimate goals to overcome this devastating disease. MicroRNAs (miRNAs) are a class of small non-coding 18 to 24 nucleotide-long RNAs that have been implicated recently in diverse cellular functions. miRNAs regulate their target genes post-transcriptionally via mRNA degradation and/or inhibition of translation. One miRNA can potentially target a wide variety of proteins regulating such as cell proliferation, cell death, cellular morphogenesis and differentiation. The relative ease by which miRNAs can be manipulated pharmacologically provides a fascinating therapeutic opportunity. One of the most appealing properties of miRNAs as therapeutic agents and probably the most important advantage in comparison with approaches targeting single genes is their ability to target multiple molecules, frequently in the context of a network, making them extremely efficient in regulating distinct cellular processes relevant to specific clinical phenotypes. We recently identified a specific miRNA signature discriminating post-transplant AKI from primary graft function. Among the identified miRNAs the most significant up-regulated miRNA during AKI was miR-182-5p. Subsequent studies identified miRNA-182-5p as main driver of AKI strongly correlated with global gene expression changes after ischemic insult. Verified target genes of miR-182-5p are involved in apoptosis, cell cycle, T-cell differentiation, proliferation and migration, pathways which balancing adaptive and maladaptive repair and regeneration processes of the kidney. The present project studied the effect of miR-182 inhibition after ischemic insult on kidney function. We show that miR-182-5p is consistently up-regulated after ischemic insult in human kidneys and animal models. Inhibition of miR-182-5p improves kidney function in rats after IRI induction. Further Antisense oligonucleotides can potentially be applied in an ex-vivo kidney machine perfusion system directly paving the way to translate pre-clinical results into human studies.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз