Selective inhibition of 5-lipoxygenase attenuates glomerulonephritis in the rat.
Three hours following injection of anti-GBM (glomerular basement membrane) antibody (10 mg/kg, i.v.) into rats, glomerular production of LTB4 was significantly increased as compared to untreated rats (497 +/- 26 vs. 244 +/- 18 pg of LTB4/mg protein). Twenty-four hours following administration of anti-GBM antibody, renal function (blood urea nitrogen, BUN; plasma creatinine, PCr; creatinine clearance, CCr; fractional excretion of sodium, FENa; fractional excretion of urea, FEUrea) was determined to be impaired proportionally to the amount of injected antibody (5 to 30 mg/kg, i.v.). In a second series of experiments, a selective 5-lipoxygenase (5-LO) inhibitor, SK&F 107649, was used to investigate the involvement of 5-LO products in the pathophysiology of anti-GBM antibody-induced glomerulonephritis. In preliminary experiments. SK&F 107649 (50 to 200 mg/kg, p.o.) inhibited ionophore (A23187)-stimulated whole blood leukotriene (LT) B4 production in a dose-dependent fashion (P < 0.05 at doses > or = 100 mg/kg). The anti-GBM antibody-mediated decrease in glomerular filtration rate (GFR) and increase in BUN and PCr were dose-dependently attenuated by SK&F 107649 (50 to 200 mg/kg, p.o. BID). These data confirm that glomerular LTB4 production is stimulated in anti-GBM antibody-induced glomerulonephritis, and demonstrate that inhibition of 5-LO by SK&F 107649 normalizes BUN and PCr and attenuate the decrease in GFR following anti-GBM antibody treatment. These results provide additional evidence for a role of 5-LO products in immune-mediated renal disease, and suggest that pharmacologic inhibition of 5-LO may be of therapeutic value.
Albrightson
C R
CR
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Short
B
B
Dytko
G
G
Zabko-Potapovich
B
B
Brickson
B
B
Adams
J L
JL
Griswold
D E
DE
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology; D001485:Basement Membrane / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000008:administration & dosage; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D007074:Immunoglobulin G; D016859:Lipoxygenase Inhibitors; D013764:Tetrahydronaphthalenes; C089093:SK&F 107649; D007975:Leukotriene B4; D014508:Urea; D001094:Arachidonate 5-Lipoxygenase