Inhibition of cyclooxygenases reduces complement-induced glomerular epithelial cell injury and proteinuria in passive Heymann nephritis.
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.
Takano
Tomoko
T
Department of Medicine, McGill University Health Centre, McGill University, Montreal, Quebec, Canada. tomoko.takano@mcgill.ca
Cybulsky
Andrey V
AV
Cupples
William A
WA
Ajikobi
David O
DO
Papillon
Joan
J
Aoudjit
Lamine
L
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
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