Superoxide dismutase mimetic drug tempol aggravates anti-GBM antibody-induced glomerulonephritis in mice.
Oxidative stress plays an important role in the pathogenesis of anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN). Superoxide dismutase (SOD) is the first line of defense against oxidative stress by converting superoxide to hydrogen peroxide (H(2)O(2)). We investigated the effect of the SOD mimetic drug tempol on anti-GBM-GN in mice. 129/svJ mice were challenged with rabbit anti-mouse-GBM sera to induce GN and subsequently divided into tempol (200 mg.kg(-1).day(-1), orally) and vehicle-treated groups. Routine histology, SOD and catalase activities, malondialdehyde (MDA), H(2)O(2), and immunohistochemical staining for neutrophils, lymphocytes, macrophages, p65-NF-kappaB, and osteopontin were performed. Mice with anti-GBM-GN had significantly reduced renal SOD and catalase activities and increased H(2)O(2) and MDA levels. Unexpectedly, tempol administration exacerbated anti-GBM-GN as evidenced by intensification of proteinuria, the presence of severe crescentic GN with leukocyte influx, and accelerated mortality in the treated group. Tempol treatment raised SOD activity and H(2)O(2) level in urine, upregulated p65-NF-kappaB and osteopontin in the kidney, but had no effect on renal catalase activity. Thus tempol aggravates anti-GBM-GN by increasing production of H(2)O(2) which is a potent NF-kappaB activator and as such can intensify inflammation and renal injury. This supposition is supported by increases seen in p65-NF-kappaB, osteopontin, and leukocyte influx in the kidneys of the tempol-treated group.
Lu
Hua
H
Department of Pathology, Univ. of Texas Southwestern Medical Center, Dallas, TX 75390-9073, USA.
Zhen
Junhui
J
Wu
Tianfu
T
Peng
Ai
A
Ye
Ting
T
Wang
Tao
T
Yu
Xueqing
X
Vaziri
Nosratola D
ND
Mohan
Chandra
C
Zhou
Xin J
XJ
D000284:Administration, Oral; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000975:Antioxidants / Q000008:administration & dosage / Q000633:toxicity*; D001323:Autoantibodies; D002374:Catalase / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D053495:Osteopontin / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012720:Severity of Illness Index; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
D000975:Antioxidants; D001323:Autoantibodies; D003497:Cyclic N-Oxides; C498144:Rela protein, mouse; D013113:Spin Labels; C506896:Spp1 protein, mouse; D051996:Transcription Factor RelA; C051951:antiglomerular basement membrane antibody; D053495:Osteopontin; D008315:Malondialdehyde; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; C001803:tempol