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Indomethacin protects permeability barrier from focal segmental glomerulosclerosis serum
Ellen T McCarthy1, Mukut Sharma
1Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. emccarth@mcw.edu
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.