title: Inhibition of cyclooxygenases reduces complement-induced glomerular epithelial cell injury and proteinuria in passive Heymann nephritis.
abstract: 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 [(3)H]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 A(2) analog 9,11-dideoxy-9alpha,11alpha-methanoepoxyprostaglandin F(2alpha) (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.
authors.affiliation: Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada. tomoko.takano@mcgill.ca
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
authors.forename: William A
authors.initials: WA
authors.lastname: Cupples
authors.forename: David O
authors.initials: DO
authors.lastname: Ajikobi
authors.forename: Joan
authors.initials: J
authors.lastname: Papillon
authors.forename: Lamine
authors.initials: L
authors.lastname: Aoudjit
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D003165:Complement System Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005663:Furans / Q000494:pharmacology / Q000627:therapeutic use; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005920:Glomerular Mesangium / Q000293:injuries* / Q000473:pathology; D005921:Glomerulonephritis / Q000150:complications* / Q000201:enzymology; D007074:Immunoglobulin G / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology / Q000627:therapeutic use; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism / Q000502:physiology; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013928:Thromboxane A2 / Q000378:metabolism
chemical_list: C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000199:Actins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D005663:Furans; D007074:Immunoglobulin G; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D013928:Thromboxane A2; D003165:Complement System Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D007213:Indomethacin