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© Copyright 2004 The British Pharmacological Society

022P GKT, University of London
Winter Meeting December 2003

The 5-lipoxygenase inhibitor zileuton reduces renal dysfunction mediated by ischaemia/reperfusion of the mouse kidney in vivo


N.S.A. Patel, 1S. Cuzzocrea, P.K. Chatterjee, 2L. Sautebin, 3D. Britti & C. Thiemermann, Dept. of Experimental Medicine, Nephrology & Critical Care, Queen Mary - University of London, Charterhouse Square, London, 1Institute of Pharmacology, University of Messina, Italy, 2Dept. of Experimental Pharmacology, University of Naples, Italy, 3Dept. of Veterinary Science, University of Teramo, Italy.

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Patel NSA
Cuzzocrea S
Chatterjee PK
Sautebin K
Britti C
Thiemermann C

Cysteine-containing leukotrienes (LTs), namely LTC4 and LTD4, are metabolites of arachidonic acid formed through the 5-lipoxygenase (5-LO) pathway. These LTs have pro-inflammatory effects, for example, they are capable of increasing postcapillary venule tone and permeability, thus causing oedema. The precursor to the cysteinyl-LTs, LTB4, is able to facilitate the transmigration of polymorphonuclear leukocytes (PMNs) into tissues. LTB4 is a key mediator involved in PMN accumulation and renal dysfunction in a rat model of ischaemia/reperfusion (I/R) injury (Noiri et al., 2000). Therefore, the present study investigated the role of 5-LO in a murine model of I/R injury.

Thirty-nine male C57BL/6J wild-type (WT) and 11 5-LO-/- mice (25-30g) were anaesthetised with chloral hydrate (125 mg kg-1). After performing a midline laparotomy, mice were divided into 7 groups (Table 1). Mice undergoing I/R were subjected to bilateral clamping of the renal pedicles for 30 min followed by reperfusion for 24 h. Sham animals did not undergo bilateral renal clamping. The 5-LO inhibitor, zileuton (Zil; 1 or 3 mg kg-1) was administered 30 min prior to ischaemia and 12 hrs following reperfusion via the tail vein. Subsequent to I/R injury, the plasma creatinine level was measured and used as an indictor of glomerular function (Table 1). Plasma AST was used as a non-specific marker of renal injury (Table 1). Levels of myeloperoxidase (MPO) in kidneys were determined as an indicator of PMN infiltration
(Table 1).

TABLE 1
n
Creatinine
AST
MPO
(mg dl-1)
(iu l-1)
(U g-1)
Sham WT
9
0.16 ± 0.02*
135 ± 33*
15 ± 0.3*
Sham WT
Zil
4
0.27 ± 0.01*
157 ± 17*
15 ± 0.4*
(3 mg kg-1)
Sham
3
0.10 ± 0.03*
56 ± 7.1*
16 ± 0.4*
5-LO-/-
I/R WT
13
1.80 ± 0.05
2200 ± 225
87 ± 2.0
I/R WT Zil
6
2.15 ± 0.12*
2345 ± 223
39 ± 1.4*
(1 mg kg-1)
I/R WT Zil
7
1.41 ± 0.12*
520 ± 80*
17 ± 1.0*
(3 mg kg-1)
I/R 5-LO-/-
8
0.65 ± 0.02*
214 ± 21*
24 ± 1.8*

Data are expressed as mean ± SEM for n mice, analysed using one-way ANOVA followed by Dunnett's post test. *P<0.05 vs. I/R WT.

We show here that the degree of renal dysfunction and injury associated with renal I/R injury is attenuated in zileuton treated and 5-LO-/- mice when compared to their WT litter mates. In addition, PMN infiltration is also reduced by zileuton treatment and in 5-LO-/- mice suggesting that the LTs may play a role in the transmigration of PMN into renal tissue following I/R injury.

Noiri, E., et al., (2000) PNAS 97, 823.