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.