Delayed graft function (DGF) after kidney transplantation represents the main risk factor for allograft loss. While DGF occurs rarely after living donor transplantation, about 25% of deceased donor kidney recipients develop DGF and require dialysis within the first week after transplantation. Various molecular mechanisms have been elucidated. Pro-inflammatory response after brain death and ischemic reperfusion injury are significant factors contributing to development of DGF. Nevertheless, prevention of DGF after transplantation is desirable but still not feasible.
MicroRNAs (miRNAs) are a class of small non-coding 18 to 24 nucleotide-long RNAs involved in the regulation of diverse cellular functions and in the pathogenesis of DGF. One of the most appealing properties of miRNAs as therapeutic agents is their ability to target multiple molecules, making them extremely efficient in regulating distinct biological cell processes relevant in specific diseases. One of their members, miR-182 is strongest increased during acute renal transplant failure. miR-182 regulates approx. 50% of significantly deregulated genes in renal allograft biopsies developing DGF within the first week after transplantation. Furthermore the inhibition of miR-182 showed anti-inflammatory properties over the target gene FOXO1.
1. We will investigate whether the inhibition of miR-182 will revert transcriptional activation of genes involved in DGF in the rat donor kidney
2. To elucidate the efficacy of miR-182 antisense in preventing the incidence and duration of postischemic DGF in a rat model.
3. The third aim is to test the proposed treatment in human deceased donor kidneys, which are declined for transplantation. Machine perfusion technique (lifeport®) will be used to apply the drug into the donor kidneys ex vivo.
This study translates recent knowledge on the molecular mechanisms of DGF into a potentially applicable prophylactic intervention.
Field of science
- /natural sciences/biological sciences/genetics and heredity/rna
- /medical and health sciences/clinical medicine/transplantation
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