Inhibition of leukotriene biosynthesis improves renal function in experimental glomerulonephritis.
The development of renal dysfunction in experimental glomerulonephritis (GN) is mediated in part by enhanced leukotriene (LT) formation. In our studies the pathophysiological role of LTs was investigated through pharmacological inhibition of LT biosynthesis in a rat model of nephrotoxic serum nephritis. MK-0591, an indirect inhibitor of 5-lipoxygenase activity, was co-administered to rats injected with nephrotoxic rabbit serum, followed by assessment of renal function, morphology and microsomal LTC4 synthase activity on day 7. A significant improvement in glomerular function was noted (p < 0.05), together with a 50% reduction in proteinuria (p < 0.01) in animals receiving MK-0591 (60 mg kg-1 day-1). In addition, the fall in renal LTC4 synthase activity which occurred in nephritic rats (to 74% of control values, p < 0.01) was prevented in drug-treated animals. Based on these results, it appears that inhibition of LT biosynthesis protects against both renal impairment and alterations in LTC4 synthase activity during the development of experimental GN, and may provide a useful therapeutic adjunct in the treatment of this disease.
Petric
R
R
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Claire-Dorval, Quebec, Canada.
Ford-Hutchinson
A
A
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D005921:Glomerulonephritis / Q000188:drug therapy*; D005982:Glutathione Transferase / Q000378:metabolism*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D007677:Kidney Function Tests; D015289:Leukotrienes / Q000096:biosynthesis* / Q000652:urine; D016859:Lipoxygenase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D008861:Microsomes / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D058927:5-Lipoxygenase-Activating Proteins; C548594:Alox5ap protein, rat; D002352:Carrier Proteins; D007211:Indoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011804:Quinolines; C078266:MK 0591; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase