Indomethacin protects permeability barrier from focal segmental glomerulosclerosis serum.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
McCarthy
Ellen T
ET
Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. emccarth@mcw.edu
Sharma
Mukut
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000418:Albumins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001572:Benzofurans / Q000494:pharmacology; D002463:Cell Membrane Permeability / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000418:Albumins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001572:Benzofurans; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D016718:Arachidonic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D015232:Dinoprostone; C039936:furegrelate; D007213:Indomethacin