ono-1301 and Proteinuria

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.

Topics: Animals; Basement Membrane; Cells, Cultured; Cholesterol; Complement C3; Cyclic AMP; Cyclosporine; Endothelium, Vascular; Glomerulonephritis; Humans; Immunoglobulin G; Immunosuppressive Agents; Integrin alpha4beta1; Integrin beta1; Integrins; Kidney Glomerulus; Male; Proteinuria; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Lymphocyte Homing; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha; Umbilical Veins; Urea; Vascular Cell Adhesion Molecule-1