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Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis
Author(s) -
Wang Zhen,
Herzog Christian,
Kaushal Gur P,
Mayeux Philip R
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.766.4
Subject(s) - sepsis , perfusion , microcirculation , intravital microscopy , medicine , kidney , acute kidney injury , ligation , peritubular capillaries , pharmacology , pathology , endocrinology
Meprin A, a matrix metalloproteinase highly expressed in the kidney and reported to be an early biomarker of acute kidney injury (AKI), is thought to play an important role in several causes of AKI. To address the role of meprin A in the early microcirculatory dysfunction associated with sepsis‐induced AKI, we studied the effects of the meprin A inhibitor actinonin in the cecal ligation and puncture (CLP) model of sepsis in the mouse. Male C57BL/6 mice (40 weeks) underwent CLP with vehicle (CLPv) or actinonin at 20 mg/kg, ip (CLPact) 30 min prior to CLP. At 7h post CLP, intravital videomicroscopy was utilized to image renal cortical peritubular capillary perfusion. Actinonin prevented the fall in renal capillary perfusion. The percentage of capillaries with continuous perfusion in CLPv and CLPact were 50 ± 9% and 83 ± 10% respectively (P < .05) and the percentage with no perfusion in CLPv and CLPact were 33 ± 10% and 7 ± 2% respectively (P < .05). Capillary perfusion in CLPact was no different from sham mice. Since meprin A is known to activate the proform of IL‐1β, serum IL‐1β was used to assess the inhibitory activity of actinonin. IL‐1β levels decreased in CLPact by 36% compared to CLPv at 7h (P < .05). These data suggest that meprin A may play an important role in the microcirculatory failure associated with sepsis‐induced AKI and that actinonin should be evaluated further as a possible therapeutic agent. Supported by NIH DK075991.