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Effects of KD3-671, an angiotensin II type 1 receptor antagonist, on anti-thy-1 nephritis in rats.

Abstract
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.
AuthorsTadashi Nagamatsu, Tatsuya Oka, Toshiyuki Nagao, Yoshio Suzuki
JournalBiological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 26 Issue 6 Pg. 808-12 (Jun 2003) ISSN: 0918-6158 [Print] Japan
PMID12808291 (Publication Type: Journal Article)
Chemical References
  • Actins
  • Angiotensin II Type 1 Receptor Blockers
  • Antibodies, Monoclonal
  • Fibronectins
  • Imidazoles
  • Isoantibodies
  • KD3 671
  • Tetrazoles
  • anti-Thy antibody
  • Enalapril
Topics
  • Actins (metabolism)
  • Administration, Oral
  • Angiotensin II Type 1 Receptor Blockers
  • Animals
  • Antibodies, Monoclonal (immunology)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enalapril (administration & dosage, pharmacology, therapeutic use)
  • Fibronectins (metabolism)
  • Glomerulonephritis, Membranoproliferative (drug therapy, immunology, metabolism, pathology)
  • Imidazoles (administration & dosage, pharmacology, therapeutic use)
  • Isoantibodies (immunology)
  • Kidney Glomerulus (metabolism, pathology)
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Tetrazoles (administration & dosage, pharmacology, therapeutic use)

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