Minocycline reduces renal microvascular leakage in a rat model of ischemic renal injury.
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.
Sutton
Timothy A
TA
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, 950 W. Walnut, RII 202, Indianapolis, IN 46202, USA. tsutton2@iupui.edu
Kelly
K J
KJ
Mang
Henry E
HE
Plotkin
Zoya
Z
Sandoval
Ruben M
RM
Dagher
Pierre C
PC
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D007962:Leukocytes; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*
D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008911:Minocycline