MODULATION OF ANTIGLOMERULAR BASEMENT-MEMBRANE NEPHRITIS IN RATS BY ONO-1301, A NONPROSTANOID PROSTAGLANDIN I-2 MIMETIC COMPOUND WITH INHIBITORY ACTIVITY AGAINST THROMBOXANE A(2) SYNTHASE

The antinephritic effects of ONO-1301 l)benzylidene]-aminooxy]ethyll-1 -naphtyloxylacetic acid) on crescentic-type anti-glomerular basement m embrane (GEM) nephritis in rats were investigated. ONO-1301 was orally given to crescentic-type anti-GEM nephritic rats for 40 days after th e induction of nephritis. ONO-1301 (30 mg/kg) suppressed the elevation of protein excretion into urine. In the ONO-1301-treated rats, choles terol and urea nitrogen content in the plasma was lower than that of t he nephritic control rats. Histological observation demonstrated that ONO-1301 suppressed the incidence of crescent formation and adhesion o f capillary wall to Bowman's capsule. However, ONO-1301 failed to inhi bit the antibody production against rabbit IgG and the rat-IgG deposit ion on the GEM. The increase in very late antigen-4 (CD496, VLA-4)-pos itive cells in nephritic glomeruli was significantly reduced by ONO-13 01 treatment on day 5. cAMP-elevating agents inhibited the up-regulati on of vascular cell adhesion molecule-1 (VCAM-1) expression on the sur face of human umbilical vein endothelial cells (HUVECs) mediated by tu mor necrosis factor (TNF)-alpha. These findings suggest that the antin ephritic 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.