Tetracyclines exhibit significant anti-inflammatory properties, inhibit
matrix metalloproteinases (
MMPs), and are protective in models of
ischemia-reperfusion injury (IRI). Both inflammatory cascades and
MMP activation have been demonstrated to modulate microvascular permeability. Because increased microvascular permeability occurs during IRI in a variety of organ systems including the kidney, we hypothesized that
minocycline, a semisynthetic
tetracycline, would diminish microvascular leakage during renal IRI. To test this hypothesis, we used intravital 2-photon microscopy to examine leakage of fluorescent
dextrans from the vasculature in a rodent model of IRI.
Minocycline significantly reduced the extent of
dextran (500 kDa) leakage from the renal microvasculature 24 h after
ischemia. Although
minocycline diminished leukocyte accumulation in the kidney following
ischemia, areas of leukocyte accumulation did not correlate with areas of microvascular permeability in either the saline- or
minocycline-pretreated animals.
Minocycline diminished the perivascular increase in MMP-2 and MMP-9, as well as the increase in MMP-2 activity 24 h after
ischemia.
ABT-518, a specific inhibitor of MMP-2 and MMP-9, also significantly reduced the extent of
dextran (500 kDa) leakage from the renal microvasculature 24 h after
ischemia. Our results indicate that
minocycline mitigates the renal microvascular permeability defect following IRI. This effect is spatially distinct from the effect of
minocycline on leukocyte accumulation and may be related to diminished activity of
MMPs on the integrity of the perivascular matrix.