15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Glomerulosclerosis--Focal-Segmental

Eicosanoids are believed to play a role in the pathophysiology of several models of glomerular disease. The cyclooxygenase inhibitor indomethacin reduces proteinuria in patients with focal segmental glomerulosclerosis (FSGS) or other glomerular diseases. We have shown that sera of some patients with FSGS significantly increase glomerular albumin permeability (Palb) in an in vitro assay.. To determine the role of eicosanoids in the increased Palb caused by the FSGS factor, glomeruli were isolated from normal rats, preincubated with indomethacin, then incubated with FSGS serum or normal serum and Palb was calculated. To study the direct effect of individual eicosanoids on Palb, glomeruli were incubated with prostaglandin E2, prostaglandin F2alpha or a thromboxane A2 mimetic, and Palb was calculated. In the final set of experiments, normal glomeruli were preincubated with the thromboxane synthase inhibitor furegrelate, incubated with FSGS serum, and Palb was calculated.. Preincubation of isolated glomeruli with either the cyclooxygenase inhibitor indomethacin or the thromboxane synthase inhibitor furegrelate protected glomeruli from the increase in Palb caused by FSGS serum. Each of the three principal glomerular eicosanoids significantly increased Palb of isolated glomeruli.. These studies implicate a product of the cyclooxygenase pathway of arachidonic acid metabolism as mediating the increased Palb caused by FSGS serum in our in vitro assay and possibly the proteinuria seen in patients with FSGS.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Albumins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Benzofurans; Cell Membrane Permeability; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Enzyme Inhibitors; Glomerulosclerosis, Focal Segmental; Indomethacin; Kidney Glomerulus; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Dinoprostone; Epoprostenol; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Kidney Glomerulus; Male; Mice; Mice, Inbred ICR; Receptors, Thromboxane; Renal Circulation; Serum Albumin, Bovine; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents