Reduction of renal ischemia-reperfusion injury in 5-lipoxygenase knockout mice and by the 5-lipoxygenase inhibitor zileuton.
The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX(-/-)) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX(-/-) mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX(-/-) mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.
Patel
Nimesh S A
NS
Centre for Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary - University of London, United Kingdom.
Cuzzocrea
Salvatore
S
Chatterjee
Prabal K
PK
Di Paola
Rosanna
R
Sautebin
Lidia
L
Britti
Domenico
D
Thiemermann
Christoph
C
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D007249:Inflammation / Q000209:etiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007511:Ischemia / Q000150:complications*; D007674:Kidney Diseases / Q000150:complications; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology
D016859:Lipoxygenase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D007975:Leukotriene B4; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase; C063449:zileuton; D006918:Hydroxyurea