Preclinical evaluation of the mitochondria‐targeted antioxidant MitoTEMPO on the renal microcirculation in a pediatric model of sepsis‐induced renal injury

Abstract

Microcirculatory failure, mitochondrial dysfunction and oxidant generation are thought to be key events during sepsis that lead to multi-organ failure. Acute kidney injury is a leading cause of mortality in septic children. We developed a clinically relevant cecal ligation and puncture (CLP) sepsis model in rat pups 17-19 days old to identify and evaluate new therapeutic approaches. Analysis of the renal microcirculation using intravital video microscopy at 18 h post CLP or sham surgery showed a significant decrease in the percentage of continuously flowing capillaries (from 75% to 40%) and an increase in capillaries with no flow (from 5% to 30%). Microcirculatory failure was associated with a 2-fold increase in mitochondrial superoxide generation in renal tubules. We then performed dose-response studies to evaluate the effectiveness of the mitochondria-targeted antioxidant MitoTEMPO to reduce mitochondria superoxide and to improve renal microcirculation. MitoTEMPO was administered at doses of 1, 3, or 10 mg/kg (ip) at the time of CLP or sham surgery. Superoxide and perfusion were measured at 18 h. MitoTEMPO produced dose-dependent decreases in mitochondrial superoxide and increases in microcirculatory perfusion with 3 mg/kg being the lowest most efficacious dose to preserve the renal microcirculation. These findings suggest a previously unrecognized link between mitochondrial oxidants in the renal tubule epithelium and the regulation of microvascular perfusion. The protective effect of MitoTEMPO in the kidney suggests that agents like it should be evaluated further for their effectiveness at reducing sepsis-induced multi-organ failure. Supported by T32 GM106999 and AHA PRE20450050.