Effects of KD3-671, an angiotensin II type 1 receptor antagonist, on anti-thy-1 nephritis in rats.
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.
Nagamatsu
Tadashi
T
Department of Pharmacology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan. nagamats@ccmfs.meijo-u.ac.jp
Oka
Tatsuya
T
Nagao
Toshiyuki
T
Suzuki
Yoshio
Y
D000199:Actins / Q000378:metabolism; D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005353:Fibronectins / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007518:Isoantibodies / Q000276:immunology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D000911:Antibodies, Monoclonal; D005353:Fibronectins; D007093:Imidazoles; D007518:Isoantibodies; C121117:KD3 671; D013777:Tetrazoles; C035678:anti-Thy antibody; D004656:Enalapril