title: Selective cyclooxygenase-2 inhibition impairs glomerular capillary healing in experimental glomerulonephritis.
abstract: Selective cyclooxygenase-2 (COX-2) inhibitors have anti-inflammatory activity and reduce proteinuria in experimental membranous glomerulonephritis. Antiangiogenic properties of COX-2 inhibitors were recently reported. Whether these properties are relevant to the glomerular healing process in inflammatory glomerular diseases was investigated. For evaluation of the effects of selective COX-2 inhibitors on the glomerular healing process in a rat model of mesangioproliferative glomerulonephritis (induced by anti-Thy 1.1 antibody), a selective COX-2 inhibitor (rofecoxib or celecoxib) or vehicle was administered daily from day 1 after disease induction until euthanasia on day 6. Additional nephritic rats were treated with rofecoxib or vehicle from day 1 to day 10 and were monitored until day 28. Selective COX-2 inhibition led to significant increases in mesangiolysis (up to +71%) on days 2 and 6 and in albuminuria (up to 3.1-fold) on day 6. This augmentation of glomerular capillary damage was associated with rarefaction of glomerular endothelial cells, whereas the proliferation and activation of mesangial cells were not affected. No significant effects on the glomerular influx of polymorphonuclear neutrophils or the infiltration and proliferation of monocytes/macrophages at day 2 were noted. These effects were independent of systemic hemodynamic features, because rofecoxib did not affect systolic BP on day 2 or 5. Nephritic rats treated with rofecoxib for 10 d demonstrated persistent glomerular injury at day 28, as indicated by increased albuminuria (10-fold) and mesangial type IV collagen deposition (+24%). In normal rats, 5-d administration of rofecoxib failed to induce albuminuria or morphologic renal damage. In conclusion, selective COX-2 inhibitors impair glomerular capillary repair after mesangiolysis in rats with anti-Thy 1.1 glomerulonephritis. These data suggest that selective COX-2 inhibitors should be used with caution among patients with inflammatory endocapillary glomerular disorders.
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitahara
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Uta
authors.initials: U
authors.lastname: Kunter
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Ulf
authors.initials: U
authors.lastname: Janssen
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Matsui
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.affiliation: *Division of Nephrology and Immunology, University of Aachen, Aachen, Germany, and Department of Pathology, University of Vienna, Vienna, Austria.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
mesh_terms: D000818:Animals; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D005920:Glomerular Mesangium / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007124:Immunoenzyme Techniques; D007783:Lactones / Q000494:pharmacology / Q000633:toxicity*; D008854:Microscopy, Electron; D011720:Pyrazoles; D051381:Rats; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity*; D013450:Sulfones
chemical_list: D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D000068579:Celecoxib