Bootcongres

Delayed graft function upon kidney transplantation is closely linked to ischemia/reperfusion (IR) injury. While targeting a wide spectrum of mechanisms effectively alleviates IR injury in preclinical models, results from clinical interventions remain disappointing. This paradox may reflect fundamental differences between mice and men. Myocardial studies implicate metabolic dysregulation and failure as a large contributor to IR injury. As mice and men differ fundamentally in their metabolic rate and pathways, we hypothesized that (part of) non-translatability of IR studies reflects fundamental differences in metabolism. In this context we considered an evaluation of the metabolic response to I/R relevant. To that end we tested the applicability of NMR for metabolic profiling. We introduced (warm) kidney ischemia (cross clamping) in ancient, 12 month old C57BL/6 mice. Mice were exposed to different periods of ischemia (30 – 60 – 90 minutes ischemia) and metabolic changes were monitored. Afterwards, high resolution NMR, a state of the art technique that allows the assessment of multiple metabolic intermediates, was accomplished to achieve a metabolic profile of the ischemic kidney. During warm ischemia firstly glucose disappears and lactate rises, as a marker for anaerobic glycolysis. After that, end products of FFA metabolism increase (Triglyceride, MUFA, PUFA) and substrates of FA metabolism are depleted. Thereafter, stores of amino acids; like glutamate, aspartate and lysine were depleted during prolonged ischemia. All in all, NMR of mice kidney tissue is an excellent tool to profile the metabolic responses to ischemia. The first reaction of the kidney upon ischemia seems to be the switch to anaerobic glycolysis. Thereafter, stores of FFAs are depleted and when ischemia proceeds amino acids are used as fuel. By unraveling the metabolic response of mice kidney to ischemia, we will be able to design a more valid, reliable mouse model and therefore a preclinical model with better translatable results to the human situation. Thereby, further application of this profiling in an ischemic model of larger animals will be presented.