Preclinical evaluation of the mitochondria‐targeted antioxidant mitoquinone to treat sepsis‐induced acute kidney injury

Abstract

Sepsis is caused by a severe microbial infection and can lead to acute kidney injury (AKI). This results in a high mortality rate of 70%. No specific therapies exist for septic AKI. To test if mitochondrial injury contributes to septic AKI, we used a clinically relevant cecal ligation and puncture (CLP) murine model. At 4h and 18h after CLP, the activity of manganese superoxide dismutase was decreased 50%, suggesting decreased mitochondrial antioxidant defense. Intravital microscopy showed a 50% fall in perfusion of renal capillaries at 18h after CLP (P < 0.05 versus control mice). Also, renal mitochondrial superoxide levels were more than doubled at 18h. We hypothesize that protecting the renal mitochondria using mitochondrial specific mitoquinone (MitoQ) will attenuate sepsis induced AKI. MitoQ (10mg/kg, i.p) given at the time of sepsis restored renal perfusion, decreased mitochondrial superoxide and preserved renal morphology at 18h post CLP. MitoQ also improved survival rate. In addition, MitoQ administered in a clinically relevant delayed dosing paradigm at 6h post CLP, also protected the renal microcirculation and inhibited mitochondrial oxidant generation. These data show that mitochondrial superoxide, a previously unrecognized mediator of septic AKI, can be targeted by mitochondrial antioxidants to attenuate septic AKI, even with delayed treatment. Supported by NIH DK075991 and AHA 12PRE12040174.