Actinonin, a Meprin a Inhibitor, Protects the Renal Microcirculation During Sepsis

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Abstract
Sepsis-induced acute kidney injury occurs in 20% to 50% of septic patients and nearly doubles the mortality rate of sepsis. Because treatment in the septic patient is usually begun only after the onset of symptoms, therapy that is effective even when delayed would have the greatest impact on patient survival. The metalloproteinase meprin A, an oligomeric complex made of α- and β-subunits, is highly expressed at the brush-border membranes of the kidney and capable of degrading numerous substrates including extracellular matrix proteins and cytokines. The goal of the present study was to compare the therapeutic potential of actinonin, an inhibitor of meprin A, when administered before and after the onset of sepsis. Mice were treated with actinonin at 30 min before or 7 h after induction of sepsis by cecal ligation and puncture (CLP). Intravital videomicroscopy was used to image renal peritubular capillary perfusion and reactive nitrogen species. Actinonin treatment 30 min before CLP reduced IL-1β levels and prevented the fall in renal capillary perfusion at 7 and 18 h. Actinonin also prevented the fall in renal capillary perfusion even when administered at 7 h after CLP. In addition, even late administration of actinonin preserved renal morphology and lowered blood urea nitrogen and serum creatinine concentrations. These data suggest that agents such as actinonin should be evaluated further as possible therapeutic agents because targeting both the early systemic and later organ-damaging effects of sepsis should have the highest likelihood of success. ABBREVIATIONS-ICU-Intensive care unit; AKI-acute kidney injury; CLP-cecal ligation and puncture; RNS-reactive nitrogen species; actinonin-3-[[1-[(2-(hydroxymethyl)-1-pyrrolidinyl)carbonyl]-2-methylpropyl]carbamoyl]octanohydroxamic acid; FITC-dextran-fluorescein isothiocyanate-dextran; DHR-2-(3,6-diamino-9H-xanthen-9-yl)-benzoic acid-methyl ester; IVVM-intravital videomicroscopy; NOx-nitrate + nitrite; PAS-periodic acid-Schiff; BUN-blood urea nitrogen; RBC-red blood cell