engleski

Inhibition of Cytochrome P450 ω -Hydroxylase Improves Renal Function in Endotoxemic Mice

20-Hydroxyeicosatetraenoic acid (20-HETE), a metabolite of arachidonic acid generated by cytochrome P450 (CYP450)--hydroxylases, is a potent renal vasoconstrictor. Its role in endotoxemic acute renal failure is unknown. In the present study the effect of inhibition of 20-HETE formation by HET0016 (HET), a selective inhibitor of CYP450 -hydroxylase on renal function was assessed in a low-dose, normotensive model of endotoxic acute renal failure in mice. There were four groups of mice: control, HET-treated control, LPS-treated and LPS+HET- treated mice. Adult female C57Bl6 mice were injected with 1 mg/kg i.p. of E. coli endotoxin (LPS) 24h prior to determination of glomerular filtration rate (GFR), renal plasma flow (RPF) and mean arterial blood pressure (MAP). HET-treated mice received HET (5 mg/kg i.p. b.i.d.) starting with the first dose at the same time as LPS, or saline (in the control mice). HET did not affect MAP in either control (83.9 2.6 vs. 84.00 6.0 con. vs. HET ; N.S.) or LPS-treated mice (83.3 2 vs. 89.0 4 mmHg, LPS vs. LPS+HET, N.S.). LPS significantly decreased GFR compared to control mice (0.83 0.10 vs. 1.14 0.13 ml/min/100 g BW ; p<0.05, LPS vs. con.). Treatment with HET0016 did not significantly affect GFR in control mice (0.97 0.15 ml/min/100 gBW), but it improved GFR in LPS-treated mice to the similar value as in control mice (1.08 0.11 vs. 1.14 0.13 ml/min/100 g BW, LPS+HET vs. con ; N.S.). Similarly, RPF, which was decreased in LPS-treated mice (2.79 0.28 vs. 3.86 0.48 ml/min 100 gBW, LPS vs. con. ; p<0.05) was normalized in LPS-treated mice given HET0016 (3.78 0.36 vs. 3.86 0.48 ml/min 100 gBW ; N.S., LPS+HET vs. con.). HET0016 did not affect RPF in the control mice (3.72 0.65 vs. 3.86 0.48 ml/min 100 gBW ; N.S., HET vs. con). In conclusion, our results suggest the pathophysiologic role of 20-HETE in the renal vasoconstriction in endotoxemic mice. Inhibition of 20-HETE formation improves renal function in endotoxic acute renal failure in mice.

sepsis; acute renal failure; cytochrome P450

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