Delayed treatment with actinonin, a meprin A inhibitor, protects the renal microcirculation and renal function during sepsis in mice

Abstract

Meprin A is a matrix metalloproteinase highly expressed in the kidney and thought to play an important role in several causes of acute kidney injury (AKI). To address the role of meprin A in the early and late phases of renal microcirculatory dysfunction associated with sepsis, we treated mice at 30 min prior to or 7 h post cecal ligation and puncture (CLP) with the meprin A inhibitor actinonin (20 mg/kg). Intravital videomicroscopy was utilized to image renal cortical peritubular capillary perfusion and reactive nitrogen species generation (RNS) using dihydrorhodamine 123 (DHR) at 18 h post CLP. Actinonin prevented the fall in renal capillary perfusion and the increase in RNS at 18 h even when administered at 7 h post CLP without affecting systemic NO generation. Importantly, even late administration of actinonin preserved renal function (as measured by BUN). These data suggest that meprin A may play an important role in the microcirculatory failure and oxidative stress associated with sepsis‐induced AKI. Moreover, actinonin should be evaluated further as a possible therapeutic agent because an agent that is protective even after the onset of sepsis would have a great impact on patient outcome. Supported by NIH DK075991.