Selective Inhibition of 5-lipoxygenase Attenuates Glomerulonephritis in the Rat

Kidney Int. 1994 May;45(5):1301-10. doi: 10.1038/ki.1994.170.

Abstract

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.

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / physiology
  • Basement Membrane / immunology
  • Dose-Response Relationship, Drug
  • Fluorescent Antibody Technique
  • Glomerular Filtration Rate
  • Glomerulonephritis / pathology
  • Glomerulonephritis / physiopathology
  • Glomerulonephritis / prevention & control*
  • Immunoglobulin G / administration & dosage
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Leukotriene B4 / antagonists & inhibitors
  • Leukotriene B4 / biosynthesis
  • Lipoxygenase Inhibitors* / pharmacology*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Sheep
  • Tetrahydronaphthalenes / pharmacology*
  • Urea / analogs & derivatives*
  • Urea / pharmacology

Substances

  • Immunoglobulin G
  • Lipoxygenase Inhibitors
  • Tetrahydronaphthalenes
  • SK&F 107649
  • Leukotriene B4
  • Urea
  • Arachidonate 5-Lipoxygenase