Modulation of anti-glomerular basement membrane nephritis in rats by ONO-1301, a non-prostanoid prostaglandin I2 mimetic compound with inhibitory activity against thromboxane A2 synthase.
The antinephritic effects of ONO-1301 ([7,8-dihydro-5-[(E)-[[a-(3-pyridyl)benzylidene]-aminooxy]ethyl]-1 -naphtyloxy]acetic acid) on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats were investigated. ONO-1301 was orally given to crescentic-type anti-GBM nephritic rats for 40 days after the induction of nephritis. ONO-1301 (30 mg/kg) suppressed the elevation of protein excretion into urine. In the ONO-1301-treated rats, cholesterol and urea nitrogen content in the plasma was lower than that of the nephritic control rats. Histological observation demonstrated that ONO-1301 suppressed the incidence of crescent formation and adhesion of capillary wall to Bowman's capsule. However, ONO-1301 failed to inhibit the antibody production against rabbit IgG and the rat-IgG deposition on the GBM. The increase in very late antigen-4 (CD49b, VLA-4)-positive cells in nephritic glomeruli was significantly reduced by ONO-1301 treatment on day 5. cAMP-elevating agents inhibited the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression on the surface of human umbilical vein endothelial cells (HUVECs) mediated by tumor necrosis factor (TNF)-alpha. These findings suggest that the antinephritic action of ONO-1301 is due to, at least in part, inhibition of intraglomerular accumulation of leukocytes through the prevention of the up-regulation of VCAM-1.
Hayashi
K
K
Department of Pharmacology, Faculty of Pharmacy, Meijo University, Tenpaku-ku, Nagoya, Japan.
Nagamatsu
T
T
Oka
T
T
Suzuki
Y
Y
D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D003176:Complement C3 / Q000032:analysis; D000242:Cyclic AMP / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D039041:Integrin alpha4beta1; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D011507:Proteinuria / Q000188:drug therapy; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism; D014508:Urea / Q000097:blood; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D003176:Complement C3; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D039041:Integrin alpha4beta1; D019012:Integrin beta1; D016023:Integrins; D011725:Pyridines; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C105488:ONO 1301; D016572:Cyclosporine; D014508:Urea; D002784:Cholesterol; D000242:Cyclic AMP; D013930:Thromboxane-A Synthase