Effects of metalloproteinase inhibition in a murine model of renal ischemia-reperfusion injury.
Ischemia-reperfusion injury (IRI) is a leading cause of acute tubular necrosis (ATN) and delayed graft function in transplanted organs. Up-regulation of matrix metalloproteinases (MMPs) propagates the microinflammatory response that drives IRI. This study sought to determine the specific effects of Marimastat (Vernalis, BB-2516), a broad spectrum MMP and TNF-alpha-converting enzyme inhibitor, on IRI-induced ATN. Mice were pretreated with Marimastat or methylcellulose vehicle for 4 d before surgery. Renal pedicles were bilaterally occluded for 30 min and allowed to reperfuse for 24 h. Baseline creatinine levels were consistent between experimental groups; however, post-IRI creatinine levels were 4-fold higher in control mice (p < 0.0001). The mean difference between the post-IRI histology grades of Marimastat-treated and control kidneys was 1.57 (p = 0.003), demonstrating more severe damage to control kidneys. Post-IRI mean (+/-SEM) MMP-2 activity rose from baseline levels in control mice (3.62 +/- 0.99); however, pretreated mice presented only a slight increase in mean MMP-2 activity (1.57 +/- 0.72) (p < 0.001). In conclusion, these data demonstrate that MMP inhibition is associated with a reduction of IRI in a murine model.
Novak
Katherine B
KB
Department of Surgery and the Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Le
Hau D
HD
Christison-Lagay
Emily R
ER
Nose
Vania
V
Doiron
Robert J
RJ
Moses
Marsha A
MA
Puder
Mark
M
D000818:Animals; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012720:Severity of Illness Index
D015415:Biomarkers; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D003404:Creatinine; C100342:marimastat; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse