Selective inhibition of 5-lipoxygenase attenuates glomerulonephritis in the rat.

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.

• Authors: C R Albrightson, B Short, G Dytko, B Zabko-Potapovich, B Brickson, J L Adams, D E Griswold
• Journal: Kidney international (Kidney Int) Vol. 45 Issue 5 Pg. 1301-10 (May 1994) ISSN: 0085-2538 [Print] United States
• PMID: 8072241 (Publication Type: Journal Article)

Chemical References

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

Topics

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