PT - JOURNAL ARTICLE AU - Tomoko Takano AU - Andrey V. Cybulsky AU - William A. Cupples AU - David O. Ajikobi AU - Joan Papillon AU - Lamine Aoudjit TI - Inhibition of Cyclooxygenases Reduces Complement-Induced Glomerular Epithelial Cell Injury and Proteinuria in Passive Heymann Nephritis AID - 10.1124/jpet.102.043604 DP - 2003 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 240--249 VI - 305 IP - 1 4099 - http://jpet.aspetjournals.org/content/305/1/240.short 4100 - http://jpet.aspetjournals.org/content/305/1/240.full SO - J Pharmacol Exp Ther2003 Apr 01; 305 AB - In the passive Heymann nephritis (PHN) model of rat membranous nephropathy, complement induces glomerular epithelial cell injury and proteinuria, which is partially mediated by eicosanoids. Glomerular cyclooxygenase (COX)-1 and -2 are up-regulated in PHN and contribute to prostanoid generation. In the current study, we address the role of COX isoforms in proteinuria, using the nonselective COX inhibitor indomethacin and the COX-2-selective inhibitor 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furanone (DFU). Four groups of rats with PHN were treated twice daily, from day 7 through 14 with vehicle, 1 mg/kg DFU, 10 mg/kg DFU, or 2 mg/kg indomethacin. Vehicle-treated rats with PHN showed significant proteinuria on day 14 (163 ± 15 mg/d, n = 19), compared with normal rats (10 ± 4 mg/d,n = 3, p < 0.001). Treatment with DFU (1 or 10 mg/kg) reduced proteinuria significantly (by ∼33%), compared with vehicle, but to a lesser extent than indomethacin (56% reduction). Glomerular eicosanoid generation was reduced significantly in the DFU and indomethacin groups, compared with vehicle. There were no significant differences among vehicle- or DFU-treated groups in [3H]inulin clearance, or in glomerular expression of COX-1 and -2. DFU did not affect the autologous immune response. In cultured rat glomerular epithelial cells, COX inhibition reduced complement-induced cytotoxicity, and this reduction was reversed by the thromboxane A2 analog 9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2α(U46619). Thus, in experimental membranous nephropathy, selective inhibition of COX-2 reduces proteinuria, without adversely affecting renal function. However, inhibition of both COX-1 and -2 is required to achieve a maximum cytoprotective and antiproteinuric effect. The American Society for Pharmacology and Experimental Therapeutics