Beneficial Effects of a Novel Inhibitor of Platelet-Derived Growth Factor Receptor Autophosphorylation in the Rat with Mesangial Proliferative Glomerulonephritis

• Published in: General pharmacology 1998-11, Vol.31 (5), p.765-773
• Main Authors: Yagi, Mikio, Kato, Shinichiro, Kobayashi, Yoshiko, Kobayashi, Nami, Iinuma, Noriko, Nakamura, Kazuhide, Kubo, Kazuo, Ohyama, Shin-Ichi, Murooka, Hideko, Shimizu, Toshiyuki, Nishitoba, Tsuyoshi, Osawa, Tatsushi, Nagano, Nobuo
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; anti-Thy-1 antibody-induced glomerulonephritis; Antibodies, Monoclonal - immunology; basic fibroblast growth factor receptor; Biological and medical sciences; Cell Division - drug effects; Cells, Cultured; Collagen - metabolism; Fibronectins - metabolism; glomerular mesangial cells; Glomerular Mesangium - drug effects; Glomerular Mesangium - metabolism; Glomerular Mesangium - pathology; Glomerulonephritis, Membranoproliferative - immunology; Glomerulonephritis, Membranoproliferative - metabolism; Glomerulonephritis, Membranoproliferative - pathology; Isoantibodies - immunology; Male; Medical sciences; Mice; Pharmacology. Drug treatments; Phosphorylation; Phosphotransferases - metabolism; platelet-derived growth factor receptor autophosphorylation inhibitor; Quinoline derivative; Quinolines - pharmacology; Rats; Rats, Inbred WKY; Receptor, Platelet-Derived Growth Factor beta; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Platelet-Derived Growth Factor - blood; Receptors, Platelet-Derived Growth Factor - metabolism; Sclerosis; T-Lymphocytes - immunology; Thymidine - metabolism; Urinary system
• ISSN: 0306-3623; 1879-0011
• DOI: 10.1016/S0306-3623(98)00104-9

1. Our original compound, Ki6896 ((4- t-butylphenyl){4-[(6,7-dimethoxy-4-quinolyl) oxy]phenyl} methanone) strongly inhibited the autophosphorylation of platelet-derived growth factor (PDGF) β-receptor (IC 50=0.31 μM) and that of basic fibroblast growth factor receptor (IC 50=3.1 μM), whereas it did not inhibit some other kinases. 2. The [ 3H]thymidine incorporation and the growth of mesangial cells under the stimulation of PDGF were inhibited by Ki6896 in a dose-dependent manner. 3. In the mesangial proliferative glomerulonephritis rats induced by anti-Thy-1 monoclonal antibody, glomerulosclerosis was ameliorated and the number of glomerular proliferating cells was decreased by the daily administration of Ki6896. However, the accumulation of type I collagen and fibronectin in the glomeruli was not suppressed by Ki6896.