We examined the effects of
KD3-671 (2-propyl-8-oxo-1-[(2'-(H-
tetrazole-5-yl)
biphenyl-4-yl)methyl]-4,5,6,7-tetrahydrocycloheptimidazole), an
angiotensin II type1 receptor antagonist, on an experimental rat model of mesangioproliferative
glomerulonephritis,
anti-Thy-1 nephritis.
Anti-Thy-1 nephritis was induced by
intravenous injection of 300 microg/kg of anti-Thy-1.1
monoclonal antibody into rats.
KD3-671 (3, 10, 30 mg/kg per day) or
enalapril (30 mg/kg per day), an
angiotensin II converting
enzyme inhibitor, was given p.o. once daily from the day before the antibody injection (the 1st day) to the 15th day after.
KD3-671 significantly inhibited an increase in the number of total and
proliferating cell nuclear antigen-positive cells and the deposition of alpha-smooth muscle actin and
fibronectin in the glomeruli of nephritic rats, but
enalapril (30 mg/kg per day) suppressed only the number of total cells and the deposition of alpha-smooth muscle actin in the glomeruli. Moreover, to elucidate the effect of
KD3-671 on matrix deposition in the glomeruli, we measured the production of
fibronectin in isolated glomeruli obtained from
anti-Thy-1 nephritic rats. The glomeruli in
anti-Thy-1 nephritic rats produced more
fibronectin than that in control rats.
KD3-671 (10(-8), 10(-7), 10(-6) M) dose-dependently attenuated
fibronectin production in isolated nephritic glomeruli. These findings suggest that
KD3-671 may be an effective agent for the treatment of mesangioproliferative
glomerulonephritis.