Modulation of anti-glomerular basement membrane nephritis in rats by ONO-1301, a non-prostanoid prostaglandin I-2 mimetic compound with inhibitory activity against thromboxane A(2) synthase

The antinephritic effects of ONO-1301 ([7,8-dihydro-5-[(E)-(3-pyridyl)benzylidene]-aminooxy]ethyll-1-naphtyloxylacetic acid) on crescentic-type anti-glomerular basement membrane (GEM) nephritis in rats were investigated. ONO-1301 was orally given to crescentic-type anti-GEM 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 GEM. The increase in very late antigen-4 (CD496, 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.