SELECTIVE-INHIBITION OF 5-LIPOXYGENASE ATTENUATES GLOMERULONEPHRITIS IN THE RAT

Three hours following injection of anti-GBM (glomerular basement membr ane) antibody (10 mg/kg, i.v.) into rats, glomerular production of LTB (4) was significantly increased as compared to untreated rats (497 +/- 26 vs. 244 +/- 18 pg of LTB(4)/mg protein). Twenty-four hours followi ng administration of anti-GBM antibody, renal function (blood urea nit rogen, BUN; plasma creatinine, P-Cr; creatinine clearance, C-Cr; fract ional excretion of sodium, FE(Na); fractional excretion of urea, FE(Ur ea)) was determined to be impaired proportionally to the amount of inj ected antibody (5 to 30 mg/kg, i.v.). In a second series of experiment s, 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 exper iments, SK&F 107649 (50 to 200 mg/kg, p.o.) inhibited ionophore (A2318 7)-stimulated whole blood leukotriene (LT) B-4 production in a dose-de pendent fashion (P < 0.05 at doses greater than or equal to 100 mg/kg) . The anti-GBM antibody-mediated decrease in glomerular filtration rat e (GFR) and increase in BUN and P-Cr were dose-dependently attenuated by SK&F 107649 (50 to 200 mg/kg, p.o. BID). These data confirm that gl omerular LTB(4) production is stimulated in anti-GBM antibody-induced glomerulonephritis, and demonstrate that inhibition of 5-LO by SK&F 10 7649 normalizes BUN and P-Cr and attenuate the decrease in GFR followi ng anti-GBM antibody treatment. These results provide additional evide nce for a role of 5-LO products in immune-mediated renal disease, and suggest that pharmacologic inhibition of 5-LO may be of therapeutic va lue.