Thromboxane A₂ Interferes with a Disposal Process of Aggregated Protein in Glomeruli

Abstract

Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were undertaken to determine if thromboxane A₂ (TXA₂) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumulated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA₂, prostaglandin E₂ (PGE₂) and prostaglandin I₂ concomitantly increased with the decrease of a-BSA in the glomeruli. TXA₂ synthase inhibitors and TXA₂ receptor antagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly increased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA₂ synthase inhibitors decreased TXA2 production in the glomeruli. TXA₂ synthase inhibitors and TXA₂ receptor antagonists did not influence the generation of PGE₂. The TXA₂ analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA₂ interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA₂ may be an effective intervention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.